Novel amido derivatives and their use as positive allosteric modulators of metabotropic glutamate receptors

ABSTRACT

The present invention relates to novel compounds of Formula (I), wherein X 1 , X 2 , X 3 , X 4 , A m  and B n  are defined as in Formula (I); invention compounds are modulators of metabotropic glutamate receptors—subtype 4 (“mGluR4”) which are useful for the treatment or prevention of central nervous system disorders as well as other disorders modulated by mGluR4 receptors. 
     
       
         
         
             
             
         
       
     
     The invention is also directed to pharmaceutical compositions and the use of such compounds in the manufacture of medicaments, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR4 is involved.

This application is a continuation of U.S. application Ser. No.12/452,601, which is a national stage of international applicationPCT/EP2008/059043 filed Jul. 10, 2008, which claims the benefit under 35U.S.C. 119(a) and 365(b) of UK application no. 0713686.4, filed Jul. 13,2007.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds of Formula (I), whereinX¹, X², X³, X⁴, A^(m) and B^(n) are defined as in Formula (I); inventioncompounds are modulators of metabotropic glutamate receptors—subtype 4(“mGluR4”) which are useful for the treatment or prevention of centralnervous system disorders as well as other disorders modulated by mGluR4receptors. The invention is also directed to pharmaceutical compositionsand the use of such compounds in the manufacture of medicaments, as wellas to the use of such compounds for the prevention and treatment of suchdiseases in which mGluR4 is involved.

BACKGROUND OF THE INVENTION

Glutamate is the major amino-acid transmitter in the mammalian centralnervous system (CNS). Glutamate plays a major role in numerousphysiological functions, such as learning and memory but also sensoryperception, development of synaptic plasticity, motor control,respiration and regulation of cardiovascular function. Furthermore,glutamate is at the center of several different neurological andpsychiatric diseases, where there is an imbalance in glutamatergicneurotransmission.

Glutamate mediates synaptic neurotransmission through the activation ofionotropic glutamate receptor channels (iGluRs), namely the NMDA, AMPAand kainate receptors which are responsible for fast excitatorytransmission (Nakanishi et al., (1998) Brain Res Rev., 26:230-235).

In addition, glutamate activates metabotropic glutamate receptors(mGluRs) which have a more modulatory role that contributes to thefine-tuning of synaptic efficacy.

The mGluRs are G protein-coupled receptors (GPCRs) withseven-transmembrane spanning domains and belong to GPCR family 3 alongwith the calcium-sensing, GABAb and pheromone receptors.

The mGluR family is composed of eight members. They are classified intothree groups (group I comprising mGluR1 and mGluR5; group II comprisingmGluR2 and mGluR3; group III comprising mGluR4, mGluR6, mGluR7 andmGluR8) according to sequence homology, pharmacological profile andnature of intracellular signalling cascades activated (Schoepp et al.(1999) Neuropharmacology, 38:1431-76).

Glutamate activates the mGluRs through binding to the largeextracellular amino-terminal domain of the receptor, herein called theorthosteric binding site. This activation induces a conformationalchange of the receptor which results in the activation of the G-proteinand intracellular signalling pathways.

In the central nervous system, mGluR4 receptors are expressed mostintensely in the cerebellar cortex, basal ganglia, sensory relay nucleiof the thalamus and hippocampus (Bradley et al. (1999) Journal ofComparative Neurology, 407:33-46; Corti et al. (2002) Neuroscience,110:403-420). The mGluR4 subtype is negatively coupled to adenylatecyclase via activation of the Gαi/o protein, is expressed primarily onpresynaptic terminals, functioning as an autoreceptor or heteroceptorand activation of mGluR4 leads to decreases in transmitter release frompresynaptic terminals (Corti et al. (2002) Neuroscience, 110:403-420;Millan et al. (2002) Journal of Biological Chemistry 277:47796-47803;Valenti et al. (2003) Journal of Neuroscience 23:72218-7226).

Orthosteric agonists of mGluR4 are not selective and activate the otherGroup III mGluRs (Schoepp et al. (1999) Neuropharmacology 38:1431-1476).The Group III orthosteric agonist L-AP4 was able to reduce motordeficits in animal models of Parkinson's disease (Valenti et al. (2003)J. Neurosci. 23:7218-7226) and decrease excitotoxicity (Bruno et al.(2000) J. Neurosci. 20; 6413-6420) and these effects appear to bemediated through mGluR4 (Marino et al. (2005) Curr. Topics Med. Chem.5:885-895). In addition to LAP-4, ACPT-1, another selective group IIImGluR agonist has been shown to caused a dose-and-structure dependantdecrease in haloperidol-induced catalepsy and attenuatedhaloperidol-increased Proenkephalin mRNA expression in the striatum(Konieczny et al. 2007). Furthemore, Lopez et al. (2007, J Neuroscience)have shown that bilateral infusions of ACPT-I or LAP-4 into the globuspallidus fully reversed the severe akinetic deficits produced by6-hydroxydopamine lesions of nigrostriatal dopamine neurons in areaction-time task without affecting the performance of controls. Inaddition, the reversal of haloperidol-induced catalepsy by intrapallidalACPT-1 was prevented by concomitant administration of a selective groupIII receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine.The opposite effects produced by group III mGluR activation in the SNrstrongly suggest a role of mGluR4 rather than others mGluR receptorsub-types in normalizing basal ganglia activity (Lopez et al. 2007).

These results suggest that, among mGluRs subtypes, mGluR4 is believed tobe the most interesting novel drug target for the treatment ofParkinson's disease (for a review see Conn et al. Nature ReviewNeuroscience 2005).

Symptoms of Parkinson's disease appear to be due to an imbalance in thedirect and indirect output pathways of the basal ganglia and reductionof transmission at the inhibitory GABAergic striato-pallidal synapse inthe indirect pathway may result in alleviation of these symptoms (Marinoet al. (2002) Amino Acids, 23:185-191).

mGluR4 is more abundant in striato-pallidal synapses than instriato-nigral synapses, and its localization suggests function as apresynaptic heteroceptor on GABAergic neurons (Bradley et al. (1999)Journal of Comparative Neurology, 407:33-46) suggesting that selectiveactivation or positive modulation of mGluR4 would decrease GABA releasein this synapse thereby decreasing output of the indirect pathway andreducing or eliminating the Parkinson's disease symptoms.

A new avenue for developing selective compounds acting at mGluRs is toidentify molecules that act through allosteric mechanisms, modulatingthe receptor by binding to a site different from the highly conservedorthosteric binding site.

Positive allosteric modulators of mGluRs have emerged recently as novelpharmacological entities offering this attractive alternative. This typeof molecule has been discovered for mGluR1, mGluR2, mGluR4, mGluR5,mGluR7 and mGluR8 (Knoflach F. et al. (2001) Proc. Natl. Acad. Sci.USA., 98:13402-13407; Johnson K et al. (2002) Neuropharmacology, 43:291;O'Brien J. A. et al. (2003) Mol. Pharmacol., 64:731-40; Johnson M. P. etal. (2003) J. Med. Chem., 46:3189-92; Marino M. J. et al. (2003) Proc.Natl. Acad. Sci. USA., 100:13668-73; Mitsukawa K. et al. (2005) ProcNatl Acad Sci USA 102(51):18712-7; Wilson J. et al. (2005)Neuropharmacology 49:278; for a review see Mutel V. (2002) Expert Opin.Ther. Patents, 12:1-8; Kew J. N. (2004) Pharmacol. Ther., 104(3):233-44;Johnson M. P. et al. (2004) Biochem. Soc. Trans., 32:881-7; recentlyRitzen A., Mathiesen, J. M., and Thomsen C. (2005) Basic Clin.Pharmacol. Toxicol. 97:202-13).

In particular molecules have been described as mGluR4 positiveallosteric modulators (Maj et al. (2003) Neuropharmacology 45:895-906;Mathiesen et al. (2003) British Journal of Pharmacology 138:1026-1030).It has been demonstrated that such molecules have been characterized inin vitro systems as well as in rat brain slices where they potentiatedthe effect of LAP-4 in inhibiting transmission at the striatopallidalsynapse. These compounds do not activate the receptor by themselves(Marino et al. (2003) Proc. Nat. Acad. Sci. USA 100:13668-13673).Rather, they enable the receptor to produce a maximal response to aconcentration of glutamate or the Group III orthosteric agonist L-AP4which by itself induces a minimal response.

PHCCC, a positive allosteric modulator of mGluR4 not active on othersmGluRs (Maj et al. (2003) Neuropharmacology 45:895-906), has been shownto be efficacious in animal models of Parkinson's disease thusrepresenting a potential novel therapeutic approach for Parkinson'sdisease as well as for other motor disorders and disturbances (Marino etal. (2003) Proc. Nat. Acad. Sci. USA 100:13668-13673), neurodegenerationin Parkinson's disease (Marino et al. (2005) Curr. Topics Med. Chem.5:885-895; Valenti et al. (2005) J. Pharmacol. Exp. Ther. 313:1296-1304;Vernon et al. (2005) Eur. J. Neurosci. 22:1799-1806, Battaglia et al.(2006) J. Neurosci. 26:7222-7229), and neurodegeneration in Alzheimer'sdisease or due to ischemic or traumatic insult (Maj et al. (2003)Neuropharmacology 45:895-906).

PHCCC also has been shown to be active in animal model of anxiety(Stachowicz et al. (2004) Eur J Pharmacol 498:153-156). Previously,ACPT-1 has been showed to produce a dose-dependent anti-conflict effectafter intrahippocampal administration and anti-depressant-like effectsin rats after intracerebroventricular administration (Tatarczynska etal., 2002)

Activation of mGluR4 receptors which are expressed in α- and F cells inthe islets of Langerhans inhibits glucagon secretion. Molecules whichactivate or potentiate agonist activity of these receptors may be aneffective treatment for hyperglycemia, one of the symptoms of type 2diabetes (Uehara et al. (2004) Diabetes 53:998-1006).

The β-chemokine RANTES is importantly involved in neuronal inflammationand has been implicated in the pathophysiology of multiple sclerosis.Activation of Group III mGluRs with L-AP4 reduced the synthesis andrelease RANTES in wild-type cultured astrocytes, whereas the ability ofL-AP4 to inhibit RANTES was greatly decreased in astrocyte cultures frommGluR4 knockout mice (Besong et al. (2002) Journal of Neuroscience,22:5403-5411). These data suggest that positive allosteric modulators ofmGluR4 may be an effective treatment for neuroinflammatory disorders ofthe central nervous system, including multiple sclerosis and relateddisorders.

Two different variants of the mGluR4 receptor are expressed in tastetissues and may function as receptors for the umami taste sensation(Monastyrskaia et al. (1999) Br. J. Pharmacol. 128:1027-1034; Toyono etal. (2002) Arch. Histol. Cytol. 65:91-96). Thus positive allostericmodulators of mGluR4 may be useful as taste agents, flavour agents,flavour enhancing agents or food additives.

There are anatomical evidence that the majority of vagal afferentsinnervating gastric muscle express group III mGluRs (mGluR4, mGluR6,mGluR7 and mGluR8) and actively transport receptors to their peripheralendings (Page et al (2005) 128:402-10). Recently, it was shown that theactivation of peripheral group III mGluRs inhibited vagal afferentsmechanosensitivity in vitro which translates into reduced triggering oftransient lower oesophagal sphincter relaxations and gastroesophagealreflux in vivo (Young et al (2008) Neuropharmacol 54:965-975). Labellingfor mGluR4 and mGluR8 was abundant in gastric vagal afferents in thenodose ganglion, at their termination sites in the nucleus tractussolitarius and in gastric vagal motoneurons. These data suggest thatpositive allosteric modulators of mGluR4 may be an effective treatmentfor gastro-esophageal reflux disease (GERD) and lower esophagealdisorders and gastro-intestinal disorders.

International patent publication WO2005/007096 describes mGluR4 receptorpositive allosteric modulator useful, alone or in combination with aneuroleptic agent, for treating or preventing movement disorders.However, none of the specifically disclosed compounds are structurallyrelated to the compounds of the invention.

-   (i) International patent publications WO2007/072090 and    WO2006/167029 describe respectively thienopyridines as modulators of    mGluR1 and mGluR5 and tricyclic compounds as mGluR1 antagonists.-   (ii) International patent publication WO2007/001975 describes    heterocyclic carboxamides as histamine H3 antagonists. International    patent publication WO2004/087048 describes benzamides as modulators    of metabotropic glutamate receptors.-   (iii) International patent publication WO2006/074884 describes    thiazole-4-carboxamides as mGluR5 receptor antagonists.-   (iv) US patent publications US2006199960 and US2006199828 describe    3-aminopyridine-2-carboxamides and 3-aminopyrazine-2-carboxamides    respectively as metabotropic glutamate receptor antagonists.-   (v) International patent publication WO99/36416 describes    furan-2-carboxamides and thiophen-2-carboxamides as modulators of    metabotropic glutamate receptors.

It has now surprisingly been found that the compounds of general formulaI show potent activity and selectivity on mGluR4 receptor. The compoundsof the invention demonstrate advantageous properties over compounds ofthe prior art. Improvements have been observed in one or more of thefollowing characteristics of the compounds of the invention: the potencyon the target, the selectivity for the target, the bioavailability, thebrain penetration, and the activity in behavioural models.

The present invention relates to a method of treating or preventing acondition in a mammal, including a human, the treatment or prevention ofwhich is affected or facilitated by the neuromodulatory effect of mGluR4modulators.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to compounds having metabotropic glutamatereceptor 4 modulator activity. In its most general compound aspect, thepresent invention provides a compound according to Formula (I),

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof,wherein:X¹ is selected from the group of N, O and S and X², X³ and X⁴ are eachindependently selected from the group of C, N, O, S and C═C representinga 5 or 6 membered heteroaryl ring which may further be substituted by 1to 3 radicals A^(m);m is an integer ranging from 1 to 3;A^(m) radicals are each independently selected from the group ofhydrogen, halogen, —CN, —OH, —NO₂, —CF₃, —SH, —NH₂ and an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylcyano,—(C₁-C₆)alkylheteroaryl, —(C₁-C₆)alkylaryl, aryl, heteroaryl,heterocycle, —(C₀-C₆)alkyl-OR¹, —O—(C₂-C₆)alkyl-OR¹,—NR¹(C₂-C₆)alkyl-OR², —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR¹—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo-OR¹, —(C₁-C₆)alkylhalo-NR¹R², —(C₀-C₆)alkyl-S—R¹,—O—(C₂-C₆)alkyl-S—R¹, —NR¹—(C₂-C₆)alkyl-S—R², —(C₀-C₆)alkyl-S(═O)—R¹,—O—(C₁-C₆)alkyl-S(═O)—R¹, —NR¹—(C₁-C₆)alkyl-S(═O)—R²,—(C₀-C₆)alkyl-S(═O)₂—R¹, —O—(C₁-C₆)alkyl-S(═O)₂—R¹,—NR¹—(C₁-C₆)alkyl-S(═O)₂—R², —(C₀-C₆)alkyl-NR¹R², —O—(C₂-C₆)alkyl-NR¹R²,—NR¹—(C₂-C₆)alkyl-NR²R³, —(C₀-C₆)alkyl-S(═O)₂NR¹R²,—O—(C₁-C₆)alkyl-S(═O)₂NR¹R², —NR¹—(C₁-C₆)alkyl-S(═O)₂NR²R³,—(C₀-C₆)alkyl-NR¹—S(═O)₂R², —O—(C₂-C₆)alkyl-NR¹—S(═O)₂R²,—NR¹—(C₂-C₆)alkyl-NR²—S(═O)₂R³, —(C₀-C₆)alkyl-C(═O)—NR¹R²,—O—(C₁-C₆)alkyl-C(═O)—NR¹R², —NR¹—(C₁-C₆)alkyl-C(═O)—NR²R³,—(C₀-C₆)alkyl-NR¹C(═O)—R², —O—(C₂-C₆)alkyl-NR¹C(═O)—R²,—NR¹—(C₂-C₆)alkyl-NR²C(═O)—R³, —(C₀-C₆)alkyl-OC(═O)—R¹,—O—(C₂-C₆)alkyl-OC(═O)—R¹, —NR¹—(C₂-C₆)alkyl-OC(═O)—R²,—(C₀-C₆)alkyl-C(═O)—OR¹, —O—(C₁-C₆)alkyl-C(═O)—OR¹,—NR¹—(C₁-C₆)alkyl-C(═O)—OR², —(C₀-C₆)alkyl-C(═O)—R¹,—O—(C₁-C₆)alkyl-C(═O)—R¹, —NR¹—(C₁-C₆)alkyl-C(═O)—R²,—(C₀-C₆)alkyl-NR¹—C(═O)—OR², —(C₀-C₆)alkyl-O—C(═O)—NR¹R²,—(C₀-C₆)alkyl-NR¹—C(═NR²)—NR³R⁴, —(C₀-C₆)alkyl-NR¹—C(═O)—NR²R³,—O—(C₂-C₆)alkyl-NR¹—C(═O)—NR²R³, —NR¹—(C₂-C₆)alkyl-NR²—C(═O)—NR³R⁴ and—(C₀-C₆)alkyl-NR¹—C(═S)—NR²R³;Any two radicals of A^(m) (A¹ and A²) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;R¹, R², R³ and R⁴ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)alkylhalo,—(C₁-C₆)alkyl, —(C₁-C₆)alkylcyano, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylcycloalkyl, heteroaryl, —(C₁-C₆)alkylheteroaryl, aryl,heterocycle and —(C₁-C₆)alkylaryl;Any two radicals of R (R¹, R², R³ or R⁴) may be taken together to forman optionally substituted 3 to 10 membered carbocyclic or heterocyclicring;n is an integer ranging from 1 to 3;B^(n) radicals are each independently selected from the group ofhydrogen, halogen, —CN, —OH, —NO₂, —CF₃, —SH, —NH₂ and an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylcyano,—(C₁-C₆)alkylheteroaryl, —(C₁-C₆)alkylaryl, aryl, heteroaryl,heterocycle, —(C₀-C₆)alkyl-OR⁵, —O—(C₂-C₆)alkyl-OR⁵,—NR⁵(C₂-C₆)alkyl-OR⁶, —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR⁵—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo-OR⁵, —(C₁-C₆)alkylhalo-NR⁵R⁶, —(C₀-C₆)alkyl-S—R⁵,—O—(C₂-C₆)alkyl-S—R⁵, —NR⁵—(C₂-C₆)alkyl-S—R⁶, —(C₀-C₆)alkyl-S(═O)—R⁵,—O—(C₁-C₆)alkyl-S(═O)—R⁵, —NR⁵—(C₁-C₆)alkyl-S(═O)—R⁶,—(C₀-C₆)alkyl-S(═O)₂—R⁵, —O—(C₁-C₆)alkyl-S(═O)₂—R⁵,—NR⁵—(C₁-C₆)alkyl-S(═O)₂—R⁶, —(C₀-C₆)alkyl-NR⁵R⁶, —O—(C₂-C₆)alkyl-NR⁵R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶R⁷, —(C₀-C₆)alkyl-S(═O)₂NR⁵R⁶,—O—(C₁-C₆)alkyl-S(═O)₂NR⁵R⁶, —NR⁵—(C₁-C₆)alkyl-S(═O)₂NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵—S(═O)₂R⁶, —O—(C₂-C₆)alkyl-NR⁵—S(═O)₂R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶—S(═O)₂R⁷, —(C₀-C₆)alkyl-C(═O)—NR⁵R⁶,—O—(C₁-C₆)alkyl-C(═O)—NR⁵R⁶, —NR⁵—(C₁-C₆)alkyl-C(═O)—NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵C(═O)—R⁶, —O—(C₂-C₆)alkyl-NR⁵C(═O)—R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶C(═O)—R⁷, —(C₀-C₆)alkyl-OC(═O)—R⁵,—O—(C₂-C₆)alkyl-OC(═O)—R⁵, —NR⁵—(C₂-C₆)alkyl-OC(═O)—R⁶,—(C₀-C₆)alkyl-C(═O)—OR⁵, —O—(C₁-C₆)alkyl-C(═O)—OR⁵,—NR⁵—(C₁-C₆)alkyl-C(═O)—OR⁶, —(C₀-C₆)alkyl-C(═O)—R⁵,—O—(C₁-C₆)alkyl-C(═O)—R⁵, —NR⁵—(C₁-C₆)alkyl-C(═O)—R⁶,—(C₀-C₆)alkyl-NR⁵—C(═O)—OR⁶, —(C₀-C₆)alkyl-O—C(═O)—NR⁵R⁶,—(C₀-C₆)alkyl-NR⁵—C(═NR⁶)—NR⁷R⁸, —(C₀-C₆)alkyl-NR⁵—C(═O)—NR⁶R⁷,—O—(C₂-C₆)alkyl-NR⁵—C(═O)—NR⁶R⁷, —NR⁵—(C₂-C₆)alkyl-NR⁶—C(═O)—NR⁷R⁸ and—(C₀-C₆)alkyl-NR⁵—C(═S)—NR⁶R⁷;Any two radicals of B^(n) (B¹ and B²) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)alkylhalo,—(C₁-C₆)alkyl, —(C₁-C₆)alkylcyano, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylcycloalkyl, heteroaryl, —(C₁-C₆)alkylheteroaryl, aryl,heterocycle and —(C₁-C₆)alkylaryl;Any two radicals of R (R⁵, R⁶, R⁷ or R⁸) may be taken together to forman optionally substituted 3 to 10 membered carbocyclic or heterocyclicring;provided that:(i)

can not be

and provided that:(ii)

can not be

when B¹ is NR⁵R⁶ and CH₂NR⁵R⁶;and provided that:(iii)

can not be

and provided that:(iv)

can not be

and provided that:(v) when X¹ is O or S and X², X³ and X⁴ are C then in

can not be

The compounds thienopyridines known as such from international patentpublications WO2007/072090 and WO2006/167029 are excluded from thepresent invention by virtue of proviso (i).

The compounds heterocyclic carboxamides known as such from internationalpatent publication WO2007/001975 and benzamides known as such frominternational patent publication WO2004/087048 are excluded from thepresent invention by virtue of proviso (ii).

The compounds thiazole-4-carboxamides known as such from internationalpatent publication WO2006/074884 are excluded from the present inventionby virtue of proviso (iii).

The compounds 3-aminopyridine-2-carboxamides and3-aminopyrazine-2-carboxamides known respectively as such from US patentpublications US2006199960 and US2006199828 are excluded from the presentinvention by virtue of proviso (iv).

The compounds furan-2-carboxamides and thiophen-2-carboxamides known assuch from international patent publication WO99/36416 are excluded fromthe present invention by virtue of proviso (v).

In one aspect of Formula (I), the invention concerns a compoundaccording to Formula (I-a),

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof,wherein:X¹ is selected from the group of N, O and S and X², X³ and X⁴ are eachindependently selected from the group of C, N, O, S and C═C representinga 5 or 6 membered heteroaryl ring which may further be substituted by 1to 3 radicals A^(m);m is an integer ranging from 1 to 3;A^(m) radicals are each independently selected from the group ofhydrogen, halogen, —CN, —OH, —NO₂, —CF₃, —SH, —NH₂ and an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylcyano,—(C₁-C₆)alkylheteroaryl, —(C₁-C₆)alkylaryl, aryl, heteroaryl,heterocycle, —(C₀-C₆)alkyl-OR¹, —O—(C₂-C₆)alkyl-OR¹,—NR¹(C₂-C₆)alkyl-OR², —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR¹—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo-OR¹, —(C₁-C₆)alkylhalo-NR¹R², —(C₀-C₆)alkyl-S—R¹,—O—(C₂-C₆)alkyl-S—R¹, —NR¹—(C₂-C₆)alkyl-S—R², —(C₀-C₆)alkyl-S(═O)—R¹,—O—(C₁-C₆)alkyl-S(═O)—R¹, —NR¹—(C₁-C₆)alkyl-S(═O)—R²,—(C₀-C₆)alkyl-S(═O)₂—R¹, —O—(C₁-C₆)alkyl-S(═O)₂—R¹,—NR¹—(C₁-C₆)alkyl-S(═O)₂—R², —(C₀-C₆)alkyl-NR¹R², —O—(C₂-C₆)alkyl-NR¹R²,—NR¹—(C₂-C₆)alkyl-NR²R³, —(C₀-C₆)alkyl-S(═O)₂NR¹R²,—O—(C₁-C₆)alkyl-S(═O)₂NR¹R², —NR¹—(C₁-C₆)alkyl-S(═O)₂NR²R³,—(C₀-C₆)alkyl-NR¹—S(═O)₂R², —O—(C₂-C₆)alkyl-NR¹—S(═O)₂R²,—NR¹—(C₂-C₆)alkyl-NR²—S(═O)₂R³, —(C₀-C₆)alkyl-C(═O)—NR¹R²,—O—(C₁-C₆)alkyl-C(═O)—NR¹R², —NR¹—(C₁-C₆)alkyl-C(═O)—NR²R³,—(C₀-C₆)alkyl-NR¹C(═O)—R², —O—(C₂-C₆)alkyl-NR¹C(═O)—R²,—NR¹—(C₂-C₆)allyl-NR²C(═O)—R³, —(C₀-C₆)alkyl-OC(═O)—R¹,—O—(C₂-C₆)alkyl-OC(═O)—R¹, —NR¹—(C₂-C₆)alkyl-OC(═O)—R²,—(C₀-C₆)alkyl-C(═O)—OR¹, —O—(C₁-C₆)alkyl-C(═O)—OR¹,—NR¹—(C₁-C₆)alkyl-C(═O)—OR², —(C₀-C₆)alkyl-C(═O)—R¹,—O—(C₁-C₆)alkyl-C(═O)—R¹, —NR¹—(C₁-C₆)alkyl-C(═O)—R²,—(C₀-C₆)alkyl-NR¹—C(═O)—OR², —(C₀-C₆)alkyl-O—C(═O)—NR¹R²,—(C₀-C₆)alkyl-NR¹—C(═NR²)—NR³R⁴, —(C₀-C₆)alkyl-NR¹—C(═O)—NR²R³,—O—(C₂-C₆)alkyl-NR¹—C(═O)—NR²R³, —NR¹—(C₂-C₆)alkyl-NR²—C(═O)—NR³R⁴ and—(C₀-C₆)alkyl-NR¹—C(═S)—NR²R³;Any two radicals of A^(m) (A¹ and A²) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;R¹, R², R³ and R⁴ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)alkylhalo,—(C₁-C₆)alkyl, —(C₁-C₆)alkylcyano, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylcycloalkyl, heteroaryl, —(C₁-C₆)alkylheteroaryl, aryl,heterocycle and —(C₁-C₆)alkylaryl;Any two radicals of R (R¹, R², R³ or R⁴) may be taken together to forman optionally substituted 3 to 10 membered carbocyclic or heterocyclicring;B¹ and B² are each independently selected from the group of hydrogen,halogen, —CN, —OH, —NO₂, —CF₃, —SH, —NH₂ and an optionally substitutedradical selected from the group of —(C₁-C₆)alkyl, —(C₁-C₆)alkylhalo,—(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylcyano, —(C₁-C₆)alkylheteroaryl,—(C₁-C₆)alkylaryl, aryl, heteroaryl, heterocycle, —(C₀-C₆)alkyl-OR⁵,—O—(C₂-C₆)alkyl-OR⁵, —NR⁵(C₂-C₆)alkyl-OR⁶,—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—NR⁵—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —(C₁-C₆)alkylhalo-OR⁵,—(C₁-C₆)alkylhalo-NR⁵R⁶, —(C₀-C₆)alkyl-S—R⁵, —O—(C₂-C₆)alkyl-S—R⁵,—NR⁵—(C₂-C₆)alkyl-S—R⁶, —(C₀-C₆)alkyl-S(═O)—R⁵,—O—(C₁-C₆)alkyl-S(═O)—R⁵, —NR⁵—(C₁-C₆)alkyl-S(═O)—R⁶,—(C₀-C₆)alkyl-S(═O)₂—R⁵, —O—(C₁-C₆)alkyl-S(═O)₂—R⁵,—NR⁵—(C₁-C₆)alkyl-S(═O)₂—R⁶, —(C₀-C₆)alkyl-NR⁵R⁶, —O—(C₂-C₆)alkyl-NR⁵R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶R⁷, —(C₀-C₆)alkyl-S(═O)₂NR⁵R⁶,—O—(C₁-C₆)alkyl-S(═O)₂NR⁵R⁶, —NR⁵—(C₁-C₆)alkyl-S(═O)₂NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵—S(═O)₂R⁶, —O—(C₂-C₆)alkyl-NR⁵—S(═O)₂R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶—S(═O)₂R⁷, —(C₀-C₆)alkyl-C(═O)—NR⁵R⁶,—O—(C₁-C₆)alkyl-C(═O)—NR⁵R⁶, —NR⁵—(C₁-C₆)alkyl-C(═O)—NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵C(═O)—R⁶, —O—(C₂-C₆)alkyl-NR⁵C(═O)—R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶C(═O)—R⁷, —(C₀-C₆)alkyl-OC(═O)—R⁵,—O—(C₂-C₆)alkyl-OC(═O)—R⁵, —NR⁵—(C₂-C₆)alkyl-OC(═O)—R⁶,—(C₀-C₆)alkyl-C(═O)—OR⁵, —O—(C₁-C₆)alkyl-C(═O)—OR⁵,—NR⁵—(C₁-C₆)alkyl-C(═O)—OR⁶, —(C₀-C₆)alkyl-C(═O)—R⁵,—O—(C₁-C₆)alkyl-C(═O)—R⁵, —NR⁵—(C₁-C₆)alkyl-C(═O)—R⁶,—(C₀-C₆)alkyl-NR⁵—C(═O)—OR⁶, —(C₀-C₆)alkyl-O—C(═O)—NR⁵R⁶,—(C₀-C₆)alkyl-NR⁵—C(═NR⁶)—NR⁷R⁸, —(C₀-C₆)alkyl-NR⁵—C(═O)—NR⁶R⁷,—O—(C₂-C₆)alkyl-NR⁵—C(═O)—NR⁶R⁷, —NR⁵—(C₂-C₆)alkyl-NR⁶—C(═O)—NR⁷R⁸ and—(C₀-C₆)alkyl-NR⁵—C(═S)—NR⁶R⁷;Any two radicals of B^(n) (B¹ and B²) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)alkylhalo,—(C₁-C₆)alkyl, —(C₁-C₆)alkylcyano, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylcycloalkyl, heteroaryl, —(C₁-C₆)alkylheteroaryl, aryl,heterocycle and —(C₁-C₆)alkylaryl;Any two radicals of R (R⁵, R⁶, R⁷ or R⁸) may be taken together to forman optionally substituted 3 to 10 membered carbocyclic or heterocyclicring;provided that according to proviso (i):

can not be

and provided that according to proviso (iii):

can not be

and provided that according to proviso (iv):

can not be

and provided that according to proviso (v):when X¹ is O or S and X², X³ and X⁴ are C then in

can not be

In a second aspect of Formula (I), the invention concerns a compoundaccording to Formula (I-b),

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof,wherein:X¹ is selected from the group of N, O and S and X², X³ and X⁴ are eachindependently selected from the group of C, N, O, S and C═C representinga 5 or 6 membered heteroaryl ring which may further be substituted by 1to 3 radicals A^(m);m is an integer ranging from 1 to 3;A^(m) radicals are each independently selected from the group ofhydrogen, halogen, —CN, —OH, —NO₂, —CF₃, —SH, —NH₂ and an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylcyano,—(C₁-C₆)alkylheteroaryl, —(C₁-C₆)alkylaryl, aryl, heteroaryl,heterocycle, —(C₀-C₆)alkyl-OR¹, —O—(C₂-C₆)alkyl-OR¹,—NR¹(C₂-C₆)alkyl-OR², —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)allyl, —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo-OR¹, —(C₁-C₆)alkylhalo-NR¹R², —(C₀-C₆)alkyl-S—R¹,—O—(C₂-C₆)alkyl-S—R¹, —NR¹—(C₂-C₆)alkyl-S—R², —(C₀-C₆)alkyl-S(═O)—R¹,—O—(C₁-C₆)alkyl-S(═O)—R¹, —NR¹—(C₁-C₆)alkyl-S(═O)—R²,—(C₀-C₆)alkyl-S(═O)₂—R¹, —O—(C₁-C₆)alkyl-S(═O)₂—R¹,—NR¹—(C₁-C₆)alkyl-S(═O)₂—R², —(C₀-C₆)alkyl-NR¹R², —O—(C₂-C₆)alkyl-NR¹R²,—NR¹—(C₂-C₆)alkyl-NR²R³, —(C₀-C₆)alkyl-S(═O)₂NR¹R²,—O—(C₁-C₆)alkyl-S(═O)₂NR¹R², —NR¹—(C₁-C₆)alkyl-S(═O)₂NR²R³,—(C₀-C₆)alkyl-NR¹—S(═O)₂R², —O—(C₂-C₆)alkyl-NR¹—S(═O)₂R²,—NR¹—(C₂-C₆)alkyl-NR²—S(═O)₂R³, —(C₀-C₆)alkyl-C(═O)—NR¹R²,—O—(C₁-C₆)alkyl-C(═O)—NR¹R², —NR¹—(C₁-C₆)alkyl-C(═O)—NR²R³,—(C₀-C₆)alkyl-NR¹C(═O)—R², —O—(C₂-C₆)alkyl-NR¹C(═O)—R²,—NR¹—(C₂-C₆)alkyl-NR²C(═O)—R³, —(C₀-C₆)alkyl-OC(═O)—R¹,—O—(C₂-C₆)alkyl-OC(═O)—R¹, —NR¹—(C₂-C₆)alkyl-OC(═O)—R²,—(C₀-C₆)alkyl-C(═O)—OR¹, —O—(C₁-C₆)alkyl-C(═O)—OR¹,—NR¹—(C₁-C₆)alkyl-C(═O)—OR², —(C₀-C₆)alkyl-C(═O)—R¹,—O—(C₁-C₆)alkyl-C(═O)—R¹, —NR¹—(C₁-C₆)alkyl-C(═O)—R²,—(C₀-C₆)alkyl-NR¹—C(═O)—OR², —(C₀-C₆)alkyl-O—C(═O)—NR¹R²,—(C₀-C₆)alkyl-NR¹—C(═NR²)—NR³R⁴, —(C₀-C₆)alkyl-NR¹—C(═O)—NR²R³,—O—(C₂-C₆)alkyl-NR¹—C(═O)—NR²R³, —NR¹—(C₂-C₆)alkyl-NR²—C(═O)—NR³R⁴ and—(C₀-C₆)alkyl-NR¹—C(═S)—NR²R³;Any two radicals of A^(m) (A¹ and A²) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;R¹, R², R³ and R⁴ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)alkylhalo,—(C₁-C₆)alkyl, —(C₁-C₆)alkylcyano, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylcycloalkyl, heteroaryl, —(C₁-C₆)alkylheteroaryl, aryl,heterocycle and —(C₁-C₆)alkylaryl;Any two radicals of R (R¹, R², R³ or R⁴) may be taken together to forman optionally substituted 3 to 10 membered carbocyclic or heterocyclicring;B¹ and B² are each independently selected from the group of hydrogen,halogen, —CN, —OH, —NO₂, —CF₃, —SH, —NH₂ and an optionally substitutedradical selected from the group of —(C₁-C₆)alkyl, —(C₁-C₆)alkylhalo,—(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylcyano, —(C₁-C₆)alkylheteroaryl,—(C₁-C₆)alkylaryl, aryl, heteroaryl, heterocycle, —(C₀-C₆)alkyl-OR⁵,—O—(C₂-C₆)alkyl-OR⁵, —NR⁵(C₂-C₆)alkyl-OR⁶,—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—NR⁵—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —(C₁-C₆)alkylhalo-OR⁵,—(C₁-C₆)alkylhalo-NR⁵R⁶, —(C₀-C₆)alkyl-S—R⁵, —O—(C₂-C₆)alkyl-S—R⁵,—NR⁵—(C₂-C₆)alkyl-S—R⁶, —(C₀-C₆)alkyl-S(═O)—R⁵,—O—(C₁-C₆)alkyl-S(═O)—R⁵, —NR⁵—(C₁-C₆)alkyl-S(═O)—R⁶,—(C₀-C₆)alkyl-S(═O)₂—R⁵, —O—(C₁-C₆)alkyl-S(═O)₂—R⁵,—NR⁵—(C₁-C₆)alkyl-S(═O)₂—R⁶, —(C₀-C₆)alkyl-NR⁵R⁶, —O—(C₂-C₆)alkyl-NR⁵R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶R⁷, —(C₀-C₆)alkyl-S(═O)₂NR⁵R⁶,—O—(C₁-C₆)alkyl-S(═O)₂NR⁵R⁶, —NR⁵—(C₁-C₆)alkyl-S(═O)₂NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵—S(═O)₂R⁶, —O—(C₂-C₆)alkyl-NR⁵—S(═O)₂R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶—S(═O)₂R⁷, —(C₀-C₆)alkyl-C(═O)—NR⁵R⁶,—O—(C₁-C₆)alkyl-C(═O)—NR⁵R⁶, —NR⁵—(C₁-C₆)alkyl-C(═O)—NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵C(═O)—R⁶, —O—(C₂-C₆)alkyl-NR⁵C(═O)—R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶C(═O)—R⁷, —(C₀-C₆)alkyl-OC(═O)—R⁵,—O—(C₂-C₆)alkyl-OC(═O)—R⁵, —NR⁵—(C₂-C₆)alkyl-OC(═O)—R⁶,—(C₀-C₆)alkyl-C(═O)—OR⁵, —O—(C₁-C₆)alkyl-C(═O)—OR⁵,—NR⁵—(C₁-C₆)alkyl-C(═O)—OR⁶, —(C₀-C₆)alkyl-C(═O)—R⁵,—O—(C₁-C₆)alkyl-C(═O)—R⁵, —NR⁵—(C₁-C₆)alkyl-C(═O)—R⁶,—(C₀-C₆)alkyl-NR⁵—C(═O)—OR⁶, —(C₀-C₆)alkyl-O—C(═O)—NR⁵R⁶,—(C₀-C₆)alkyl-NR⁵—C(═NR⁶)—NR⁷R⁸, —(C₀-C₆)alkyl-NR⁵—C(═O)—NR⁶R⁷,—O—(C₂-C₆)alkyl-NR⁵—C(═O)—NR⁶R⁷, —NR⁵—(C₂-C₆)alkyl-NR⁶—C(═O)—NR⁷R⁸ and—(C₀-C₆)alkyl-NR⁵—C(═S)—NR⁶R⁷;Any two radicals of B^(n) (B¹ and B²) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)alkylhalo,—(C₁-C₆)alkyl, —(C₁-C₆)alkylcyano, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylcycloalkyl, heteroaryl, —(C₁-C₆)alkylheteroaryl, aryl,heterocycle and —(C₁-C₆)alkylaryl;Any two radicals of R (R⁵, R⁶, R⁷ or R⁸) may be taken together to forman optionally substituted 3 to 10 membered carbocyclic or heterocyclicring;provided that according to proviso (i):

can not be

and provided that according to proviso (iii):

can not be

and provided that according to proviso (iv):

can not be

In a third aspect of Formula (I), the invention concerns a compoundaccording to Formula (I-c),

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof,wherein:X¹ is selected from the group of N, O and S and X², X³ and X⁴ are eachindependently selected from the group of C, N, O, S and C═C representinga 5 or 6 membered heteroaryl ring which may further be substituted by 1to 3 radicals A^(m);m is an integer ranging from 1 to 3;A^(m) radicals are each independently selected from the group ofhydrogen, halogen, —CN, —OH, —NO₂, —CF₃, —SH, —NH₂ and an optionallysubstituted radical selected from the group of —(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo, —(C₃-C₇)cycloalkyl, —(C₁-C₆)alkylcyano,—(C₁-C₆)alkylheteroaryl, —(C₁-C₆)alkylaryl, aryl, heteroaryl,heterocycle, —(C₀-C₆)alkyl-OR¹, —O—(C₂-C₆)alkyl-OR¹,—NR¹(C₂-C₆)alkyl-OR², —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR¹—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo-OR¹, —(C₁-C₆)alkylhalo-NR¹R², —(C₀-C₆)alkyl-S—R¹,—NR¹—(C₂-C₆)alkyl-S—R², —(C₀-C₆)alkyl-S(═O)—R¹,—O—(C₁-C₆)alkyl-S(═O)—R¹, —NR¹—(C₁-C₆)alkyl-S(═O)—R²,—(C₀-C₆)alkyl-S(═O)₂—R¹, —O(C₁-C₆)alkyl-S(═O)₂—R¹,—NR¹—(C₁-C₆)alkyl-S(═O)₂—R², —(C₀-C₆)alkyl-NR¹R², —O—(C₂-C₆)alkyl-NR¹R²,—NR¹—(C₂-C₆)alkyl-NR²R³, —(C₀-C₆)alkyl-S(═O)₂NR¹R²,—O—(C₁-C₆)alkyl-S(═O)₂NR¹R², —NR¹—(C₁-C₆)alkyl-S(═O)₂NR²R³,(C₀-C₆)alkyl-NR¹—S(═O)₂R², —O(C₂-C₆)alkyl-NR¹—S(═O)₂R²,—NR¹—(C₂-C₆)alkyl-NR²—S(═O)₂R³, —(C₀-C₆)alkyl-C(═O)—NR¹R²,—O—(C₁-C₆)alkyl-C(═O)—NR¹R², —NR¹—(C₁-C₆)alkyl-C(═O)—NR²R³,—(C₀-C₆)alkyl-NR¹C(═O)—R², —O—(C₂-C₆)alkyl-NR¹C(═O)—R²,—NR¹—(C₂-C₆)alkyl-NR²C(═O)—R³, —(C₀-C₆)alkyl-OC(═O)—R¹,—O—(C₂-C₆)alkyl-OC(═O)—R¹, —NR¹—(C₂-C₆)alkyl-OC(═O)—R²,—(C₀-C₆)alkyl-C(═O)—OR¹, —O—(C₁-C₆)alkyl-C(═O)—OR¹,—NR¹—(C₁-C₆)alkyl-C(═O)—OR², —(C₀-C₆)alkyl-C(═O)—R¹, —C₆)alkyl-C(═O)—R¹,—NR¹—(C₁-C₆)alkyl-C(═O)—R², —(C₀-C₆)alkyl-NR¹—C(═O)—OR²,—(C₀-C₆)alkyl-O—C(═O)—NR¹R², —(C₀-C₆)alkyl-NR¹—C(═NR²)—NR³R⁴,—(C₀-C₆)alkyl-NR¹—C(═O)—NR²R³, —O—(C₂-C₆)alkyl-NR¹—C(═O)—NR²R³,—NR¹—(C₂-C₆)alkyl-NR²—C(═O)—NR³R⁴ and —(C₀-C₆)alkyl-NR¹—C(═S)—NR²R³;Any two radicals of A^(m) (A¹ and A²) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring;R¹, R², R³ and R⁴ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)alkylhalo,—(C₁-C₆)alkyl, —(C₁-C₆)alkylcyano, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylcycloalkyl, heteroaryl, —(C₁-C₆)alkylheteroaryl, aryl,heterocycle and —(C₁-C₆)alkylaryl;Any two radicals of R (R¹, R², R³ or R⁴) may be taken together to forman optionally substituted 3 to 10 membered carbocyclic or heterocyclicring;B¹ is selected from the group of hydrogen, halogen, —CN, —OH, —NO₂,—CF₃, —SH, —NH₂ and an optionally substituted radical selected from thegroup of —(C₁-C₆)alkyl, —(C₁-C₆)alkylhalo, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylcyano, —(C₁-C₆)alkylheteroaryl, —(C₁-C₆)alkylaryl, aryl,heteroaryl, heterocycle, —(C₀-C₆)alkyl-OR⁵, —O—(C₂-C₆)alkyl-OR⁵,—NR⁵(C₂-C₆)alkyl-OR⁶, —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR⁵—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo-OR⁵, —(C₁-C₆)alkylhalo-NR⁵R⁶, —(C₀-C₆)alkyl-S—R⁵,—O—(C₂-C₆)alkyl-S—R⁵, —NR⁵—(C₂-C₆)alkyl-S—R⁶, —(C₀-C₆)alkyl-S(═O)—R⁵,—O—(C₁-C₆)alkyl-S(═O)—R⁵, —NR⁵—(C₁-C₆)alkyl-S(═O)—R⁶,—(C₀-C₆)alkyl-S(═O)₂—R⁵, —O—(C₁-C₆)alkyl-S(═O)₂—R⁵,—NR⁵—(C₁-C₆)alkyl-S(═O)₂—R⁶, —(C₀-C₆)alkyl-NR⁵R⁶, —O—(C₂-C₆)alkyl-NR⁵R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶R⁷, —(C₀-C₆)alkyl-S(═O)₂NR⁵R⁶,—O—(C₁-C₆)alkyl-S(═O)₂NR⁵R⁶, —NR⁵—(C₁-C₆)alkyl-S(═O)₂NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵—S(═O)₂R⁶, —O—(C₂-C₆)alkyl-NR⁵—S(═O)₂R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶—S(═O)₂R⁷, —(C₀-C₆)alkyl-C(═O)—NR⁵R⁶,—O—(C₁-C₆)alkyl-C(═O)—NR⁵R⁶, —NR⁵—(C₁-C₆)alkyl-C(═O)—NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵C(═O)—R⁶, —O—(C₂-C₆)alkyl-NR⁵C(═O)—R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶C(═O)—R⁷, —(C₀-C₆)alkyl-OC(═O)—R⁵,—O—(C₂-C₆)alkyl-OC(═O)—R⁵, —NR⁵—(C₂-C₆)alkyl-OC(═O)—R⁶,—(C₀-C₆)alkyl-C(═O)—OR⁵, —O—(C₁-C₆)alkyl-C(═O)—OR⁵,—NR⁵—(C₁-C₆)alkyl-C(═O)—OR⁶, —(C₀-C₆)alkyl-C(═O)—R⁵,—O—(C₁-C₆)alkyl-C(═O)—R⁵, —NR⁵—(C₁-C₆)alkyl-C(═O)—R⁶,—(C₀-C₆)alkyl-NR⁵—C(═O)—OR⁶, —(C₀-C₆)alkyl-O—C(═O)—NR⁵R⁶,—(C₀-C₆)alkyl-NR⁵—C(═NR⁶)—NR⁷R⁸, —(C₀-C₆)allyl-NR⁵—C(═O)—NR⁶R⁷,—O—(C₂-C₆)alkyl-NR⁵—C(═O)—NR⁶R⁷, —NR⁵—(C₂-C₆)alkyl-NR⁶—C(═O)—NR⁷R⁸ and—(C₀-C₆)alkyl-NR⁵—C(═S)—NR⁶R⁷;R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or an optionallysubstituted radical selected from the group of —(C₁-C₆)alkylhalo,—(C₁-C₆)alkyl, —(C₁-C₆)alkylcyano, —(C₃-C₇)cycloalkyl,—(C₄-C₁₀)alkylcycloalkyl, heteroaryl, —(C₁-C₆)alkylheteroaryl, aryl,heterocycle and —(C₁-C₆)alkyl aryl;Any two radicals of R (R⁵, R⁶, R⁷ or R⁸) may be taken together to forman optionally substituted 3 to 10 membered carbocyclic or heterocyclicring;Z is selected from the group of O and NR⁹; andR⁹ is hydrogen or an optionally substituted radical selected from thegroup of —(C₁-C₆)alkylhalo, —(C₁-C₆)alkyl, —(C₁-C₆)alkylcyano,—(C₃-C₇)cycloalkyl, —(C₄-C₁₀)alkylcycloalkyl, heteroaryl,—(C₁-C₆)alkylheteroaryl, aryl, heterocycle, —C(═O)alkyl,—C(═O)—(C₃-C₇)cycloalkyl —C(═O)aryl, —C(═O)heteroaryl,—C(═O)heterocycle, —C(═O)—(C₁-C₆)alkylcycloalkyl,—C(═O)—(C₁-C₆)alkylheteroaryl and —(C₁-C₆)alkylaryl.

Particular preferred compounds of the invention are compounds asmentioned in the following list (List of Particular PreferredCompounds), as well as a pharmaceutically acceptable acid or baseaddition salt thereof, a stereochemically isomeric form thereof and anN-oxide form thereof.

-   N-(3,4-dichlorophenyl)-1H-pyrrole-2-carboxamide-   N-(3-Chlorophenyl)-1H-imidazole-2-carboxamide-   N-(3-Methoxyphenyl)thiophene-2-carboxamide-   5-Methyl-N-(4-phenoxyphenyl)furan-2-carboxamide-   Furan-2-carboxylic acid    {3-[2-(4-fluoro-phenyl)-2-oxo-ethoxy]-phenyl}-amide-   N-(3-Methoxyphenyl)picolinamide-   N-(3-Methoxyphenyl)-2-methylthiazole-4-carboxamide-   N-(3-Chlorophenyl)thiophene-2-carboxamide-   5-Bromo-N-(3-methoxyphenyl)furan-2-carboxamide-   N-(3-Chlorophenyl)picolinamide-   N-(3-Methoxyphenyl)thiazole-2-carboxamide-   N-(3-(2-(3-Methoxyphenyl)-2-oxoethoxy)phenyl)furan-2-carboxamide-   N-(3-(2-Oxo-2-p-tolylethoxy)phenyl)furan-2-carboxamide-   N-(3-(2-(4-Methoxyphenyl)-2-oxoethoxy)phenyl)furan-2-carboxamide-   N-(3-(1-Oxo-1-p-tolylpropan-2-yloxy)phenyl)furan-2-carboxamide-   N-(3-(Trifluoromethoxy)phenyl)picolinamide-   N-(3-(2-(3-Chlorophenyl)-2-oxoethoxy)phenyl)picolinamide-   N-(3-(3-Phenylpropoxy)phenyl)picolinamide-   N-(3-(2-(2-Methoxyphenyl)-2-oxoethoxy)phenyl)picolinamide-   N-(3-(2-(3-Methoxyphenyl)-2-oxoethoxy)phenyl)picolinamide-   N-(3-(2-(3-Fluorophenyl)-2-oxoethoxy)phenyl)picolinamide-   N-(3-(2-(2-Chlorophenyl)-2-oxoethoxy)phenyl)picolinamide-   N-(3-Fluorophenyl)picolinamide-   N-(3-Methoxyphenyl)-5-methylisoxazole-3-carboxamide-   N-(4-Fluoro-3-methoxyphenyl)picolinamide-   N-(3-Chlorophenyl)-1H-pyrrole-2-carboxamide-   N-(3-(2-(2-Fluorophenyl)-2-oxoethoxy)phenyl)picolinamide-   N-(3-Methoxyphenyl)pyrimidine-4-carboxamide-   6-Fluoro-N-(4-fluoro-3-methoxyphenyl)picolinamide-   N-(3-Chloro-4-(pyrimidin-2-yloxy)phenyl)picolinamide-   N-(4-Fluoro-3-methoxyphenyl)thiazole-2-carboxamide-   N-(3-Chloro-4-(pyrimidin-2-yloxy)phenyl)-2-methylthiazole-4-carboxamide-   N-(3-Chloro-4-(pyrimidin-2-yloxy)phenyl)thiazole-2-carboxamide-   N-(3-Chloro-4-morpholinophenyl)picolinamide-   N-(3-Chloro-4-(pyridin-2-yloxy)phenyl)picolinamide-   N-(3-Chloro-4-(2,5-difluorophenoxy)phenyl)picolinamide-   N-(3-Chloro-4-(2-chlorophenoxy)phenyl)picolinamide-   N-(3-Chloro-4-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)picolinamide-   N-(3-Chloro-4-(4-isobutyrylpiperazin-1-yl)phenyl)picolinamide-   N-(3-Methoxy-4-(pyrimidin-2-yloxy)phenyl)picolinamide-   N-(4-(Trifluoromethoxy)phenyl)picolinamide-   N-(3-Chloro-4-(3-chlorophenoxy)phenyl)picolinamide-   N-(3-Chloro-4-(3-fluorophenoxy)phenyl)picolinamide-   N-(3-Chloro-4-(4-fluorophenoxy)phenyl)picolinamide-   N-(3-Chloro-4-(4-chlorophenoxy)phenyl)picolinamide-   N-(3-Chloro-4-(4-propionylpiperazin-1-yl)phenyl)picolinamide-   N-(4-(4-Benzoylpiperazin-1-yl)-3-chlorophenyl)picolinamide-   N-(3-Chloro-4-(4-cyanophenoxy)phenyl)picolinamide-   N-(3-Chloro-4-(3-cyanopyridin-2-yloxy)phenyl)picolinamide-   N-(4-(4-Benzylpiperazin-1-yl)-3-chlorophenyl)picolinamide

Definition of Terms

Listed below are definitions of various terms used in the specificationand claims to describe the present invention.

For the avoidance of doubt it is to be understood that in thisspecification “(C₁-C₆)” means a carbon radical having 1, 2, 3, 4, 5 or 6carbon atoms. “(C₀-C₆)” means a carbon radical having 0, 1, 2, 3, 4, 5or 6 carbon atoms. In this specification “C” means a carbon atom, “N”means a nitrogen atom, “O” means an oxygen atom and “S” means a sulphuratom.

In the case where a subscript is the integer 0 (zero) the radical towhich the subscript refers, indicates that the radical is absent, i.e.there is a direct bond between the radicals.

In this specification, unless stated otherwise, the term “bond” refersto a saturated covalent bond. When two or more bonds are adjacent to oneanother, they are assumed to be equal to one bond. For example, aradical -A-B—, wherein both A and B may be a bond, the radical isdepicting a single bond.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl radicals and may bemethyl, ethyl, n-propyl, i-propyl, n-butyl, butyl, s-butyl, t-butyl,n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, i-hexyl or t-hexyl.The term “(C₀-C₃)alkyl” refers to an alkyl radical having 0, 1, 2 or 3carbon atoms and may be methyl, ethyl, n-propyl and i-propyl.

In this specification, unless stated otherwise, the term “cycloalkyl”refers to an optionally substituted carbocycle containing noheteroatoms, including mono-, bi-, and tricyclic saturated carbocycles,as well as fused ring systems. Such fused ring systems can include onering that is partially or fully unsaturated such as a benzene ring toform fused ring systems such as benzo-fused carbocycles. Cycloalkylincludes such fused ring systems as spirofused ring systems. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,decahydronaphthalene, adamantane, indanyl, fluorenyl and1,2,3,4-tetrahydronaphthalene and the like. The term “(C₃-C₇)cycloalkyl”may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andthe like.

The term “aryl” refers to an optionally substituted monocyclic orbicyclic hydrocarbon ring system containing at least one unsaturatedaromatic ring. Examples and suitable values of the term “aryl” arephenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl, indenyl and thelike.

In this specification, unless stated otherwise, the term “heteroaryl”refers to an optionally substituted monocyclic or bicyclic unsaturated,aromatic ring system containing at least one heteroatom selectedindependently from N, O or S. Examples of “heteroaryl” may be, but arenot limited to thienyl, pyridyl, thiazolyl, isothiazolyl, furyl,pyrrolyl, triazolyl, imidazolyl, oxadiazolyl, oxazolyl, isoxazolyl,pyrazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl,thiadiazolyl, benzoimidazolyl, benzooxazolyl, benzothiazolyl,tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, benzofuryl,benzothiophenyl, thionaphthyl, indolyl, isoindolyl, pyridonyl,pyridazinyl, pyrazinyl, pyrimidinyl, quinolyl, phtalazinyl,naphthyridinyl, quinoxalinyl, quinazolyl, imidazopyridyl,oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl,thiazolopyridazinyl, cynnolyl, pteridinyl, furazanyl, benzotriazolyl,pyrazolopyridinyl and purinyl.

In this specification, unless stated otherwise, the term “alkylaryl”,“alkylheteroaryl” and “alkylcycloalkyl” refers respectively to asubstituent that is attached via the alkyl radical to an aryl,heteroaryl or cycloalkyl radical, respectively. The term“(C₁-C₆)alkylaryl” includes aryl-C₁-C₆-alkyl radicals such as benzyl,1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl,3-phenylpropyl, 1-naphthylmethyl and 2-naphthylmethyl. The term“(C₁-C₆)alkyheteroaryl” includes heteroaryl-C₁-C₆-alkyl radicals,wherein examples of heteroaryl are the same as those illustrated in theabove definition, such as 2-furylmethyl, 3-furylmethyl, 2-thienylmethyl,3-thienylmethyl, 1-imidazolylmethyl, 2-imidazolylmethyl,3-imidazolylmethyl, 2-oxazolylmethyl, 3-oxazolylmethyl,2-thiazolylmethyl, 3-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl,4-pyridylmethyl, 1-quinolylmethyl or the like.

In this specification, unless stated otherwise, the term “heterocycle”refers to an optionally substituted, monocyclic or bicyclic saturated,partially saturated or unsaturated ring system containing at least oneheteroatom selected independently from N, O and S.

In this specification, unless stated otherwise, a 5- or 6-membered ringcontaining one or more atoms independently selected from C, N, O and S,includes aromatic and heteroaromatic rings as well as carbocyclic andheterocyclic rings which may be saturated or unsaturated. Examples ofsuch rings may be, but are not limited to, furyl, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl,imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl,piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, tetrahydrothiopyranyl, oxazolidinonyl,thiomorpholinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, phenyl,cyclohexyl, cyclopentyl, cyclohexenyl and cyclopentenyl.

In this specification, unless stated otherwise, a 3- to 10-membered ringcontaining one or more atoms independently selected from C, N, O and S,includes aromatic and heteroaromatic rings as well as carbocyclic andheterocyclic rings which may be saturated or unsaturated. Examples ofsuch rings may be, but are not limited to imidazolidinyl, imidazolinyl,morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl,pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,thiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, isoxazolyl,isothiazolyl, oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl,imidazolyl, triazolyl, phenyl, cyclopropyl, aziridinyl, cyclobutyl,azetidinyl, oxadiazolyl, thiadiazolyl, tetrazolyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl,cyclooctyl and cyclooctenyl.

In this specification, unless stated otherwise, the term “halo” or“halogen” may be fluoro, chloro, bromo or iodo.

In this specification, unless stated otherwise, the term “alkylhalo”means an alkyl radical as defined above, substituted with one or morehalo radicals. The term “(C₁-C₆)alkylhalo” may include, but is notlimited to, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyland difluoroethyl. The term “O—C₁-C₆-alkylhalo” may include, but is notlimited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy andfluoroethoxy.

In this specification, unless stated otherwise, the term “alkylcyano”means an alkyl radical as defined above, substituted with one or morecyano.

In this specification, unless stated otherwise, the term “optionallysubstituted” refers to radicals further bearing one or more substituentswhich may be, but are not limited to, (C₁-C₆)alkyl, hydroxy,(C₁-C₆)alkyloxy, mercapto, aryl, heterocycle, halogen, trifluoromethyl,pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amido, amidinyl,carboxyl, carboxamide, (C₁-C₆)alkyloxycarbonyl, carbamate, sulfonamide,ester and sulfonyl.

In this specification, unless stated otherwise, the term “solvate”refers to a complex of variable stoichiometry formed by a solute (e.g. acompound of Formula (I)) and a solvent. The solvent is apharmaceutically acceptable solvent as preferably water; such solventmay not interfere with the biological activity of the solute.

In this specification, unless stated otherwise, the term “positiveallosteric modulator of mGluR4” or “allosteric modulator of mGluR4”refers also to a pharmaceutically acceptable acid or base addition saltthereof, a stereochemically isomeric form thereof and an N-oxide formthereof.

Pharmaceutical Compositions

Allosteric modulators of mGluR4 described herein, and thepharmaceutically acceptable salts, solvates and hydrates thereof can beused in pharmaceutical preparations in combination with apharmaceutically acceptable carrier or diluent. Suitablepharmaceutically acceptable carriers include inert solid fillers ordiluents and sterile aqueous or organic solutions. The allostericmodulators of mGluR4 will be present in such pharmaceutical compositionsin amounts sufficient to provide the desired dosage amount in the rangedescribed herein. Techniques for formulation and administration of thecompounds of the instant invention can be found in Remington: theScience and Practice of Pharmacy, 19^(th) edition, Mack Publishing Co.,Easton, Pa. (1995).

The amount of allosteric modulators of mGluR4, administered to thesubject will depend on the type and severity of the disease or conditionand on the characteristics of the subject, such as general health, age,sex, body weight and tolerance to drugs. The skilled artisan will beable to determine appropriate dosages depending on these and otherfactors. Effective dosages for commonly used CNS drugs are well known tothe skilled person. The total daily dose usually ranges from about0.05-2000 mg.

The present invention relates to pharmaceutical compositions whichprovide from about 0.01 to 1000 mg of the active ingredient per unitdose. The compositions may be administered by any suitable route. Forexample orally in the form of capsules, etc. . . . , parenterally in theform of solutions for injection, topically in the form of onguents orlotions, ocularly in the form of eye-drops, rectally in the form ofsuppositories, intranasally or transcutaneously in the form of deliverysystem like patches.

For oral administration, the allosteric modulators of mGluR4 thereof canbe combined with a suitable solid or liquid carrier or diluent to formcapsules, tablets, pills, powders, syrups, solutions, suspensions andthe like.

The tablets, pills, capsules, and the like contain from about 0.01 toabout 99 weight percent of the active ingredient and a binder such asgum tragacanth, acacias, corn starch or gelatin; excipients such asdicalcium phosphate; a disintegrating agent such as corn starch, potatostarch, alginic acid, a lubricant such as magnesium stearate; and asweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

For parenteral administration the disclosed allosteric modulators ofmGluR4 can be combined with sterile aqueous or organic media to forminjectable solutions or suspensions. For example, solutions in sesame orpeanut oil, aqueous propylene glycol and the like can be used, as wellas aqueous solutions of water-soluble pharmaceutically-acceptable saltsof the compounds. Dispersions can also be prepared in glycerol, liquidpolyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

In addition, to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation, for example, subcutaneously orintramuscularly or by intramuscular injection. Thus, for example, as anemulsion in an acceptable oil, or ion exchange resins, or as sparinglysoluble derivatives, for example, as sparingly soluble salts.

Preferably disclosed allosteric modulators of mGluR4 or pharmaceuticalformulations containing these compounds are in unit dosage form foradministration to a mammal. The unit dosage form can be any unit dosageform known in the art including, for example, a capsule, an IV bag, atablet, or a vial. The quantity of active ingredient in a unit dose ofcomposition is an effective amount and may be varied according to theparticular treatment involved. It may be appreciated that it may benecessary to make routine variations to the dosage depending on the ageand condition of the patient. The dosage will also depend on the routeof administration which may be by a variety of routes including oral,aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular,intraperitoneal and intranasal.

Methods of Synthesis

The compounds according to the invention, in particular the compoundsaccording to the Formula (I), (I-a), (I-b), (I-c) and (I-d), may beprepared by methods known in the art of organic synthesis as set forthin part by the following synthesis schemes. In all of the schemesdescribed below, it is well understood that protecting groups forsensitive or reactive groups are employed where necessary in accordancewith general principles of chemistry. Protecting groups are manipulatedaccording to standard methods of organic synthesis (Green T. W. and WutsP. G. M. (1991) Protecting Groups in Organic Synthesis, John Wiley &Sons). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection of process as well as the reaction conditions andorder of their execution shall be consistent with the preparation ofcompounds of Formula (I), (I-a), (I-b), (I-c) and (I-d).

The compounds according to the invention may be represented as a mixtureof enantiomers, which may be resolved into the individual pure R- orS-enantiomers. If for instance, a particular enantiomer is required, itmay be prepared by asymmetric synthesis or by derivation with a chiralauxiliary, where the resulting diastereomeric mixture is separated andthe auxiliary group cleaved to provide the pure desired enantiomers.Alternatively, where the molecule contains a basic functional group suchas an amino or an acidic functional group such as carboxyl, thisresolution may be conveniently performed by fractional crystallizationfrom various solvents as the salts of an optical active acid or by othermethods known in the literature (e.g. chiral column chromatography).

Resolution of the final product, an intermediate or a starting materialmay be performed by any suitable method known in the art (Eliel E. L.,Wilen S. H. and Mander L. N. (1984) Stereochemistry of OrganicCompounds, Wiley-Interscience).

Many of the heterocyclic compounds of the invention can be preparedusing synthetic routes well known in the art (Katrizky A. R. and. ReesC. W. (1984) Comprehensive Heterocyclic Chemistry, Pergamon Press).

The product from the reaction can be isolated and purified employingstandard techniques, such as extraction, chromatography, crystallizationand distillation.

The compounds of the invention may be prepared by general route ofsynthesis as disclosed in the following methods.

In one embodiment of the present invention compounds of Formula (I) maybe prepared according to the synthetic sequences illustrated inScheme 1. Acid chloride g1 can be generated from carboxylic acid g3 inthe presence of a reagent such as thionyl chloride or oxalyl chloride.Then g1 may be coupled with the primary amine g2 in the presence of abase such as Et₃N or DIEA in a suitable solvent.

Amide g4 can also be obtained from the reaction of carboxylic acid g3and the primary amine g2 (Scheme 1). The reaction may be promoted by acoupling agent known in the art of organic synthesis such as EDCI(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide), in a suitable solvent(e.g. THF, DCM, DMF). Typically, a co-catalyst such as HOBT(hydroxybenzotriazole) will also be present in the reaction mixture. Thereaction typically proceeds at ambient temperature for a time in therange of about 4 up to 12 hours.

For a person skilled in the art of organic chemistry it is wellunderstood that amide g5 can be alkylated using either B²X (where X isCl, Br or I) in the presence of a base such as K₂CO₃, Cs₂CO₃ or NaH in asuitable solvent such as acetone, DMF or THF to yield g6 (Scheme 2).

In another embodiment of the present invention compounds of Formula(I-b) may be prepared according to the synthetic sequences illustratedin Scheme 3. p-Nitro-phenoxy g11 can be obtained from substitution onfluorophenyl g7 by hydroxyl compounds like g8 or by p-nitrophenol g9 onbromide compounds g10 in the presence of a base such as Cs₂CO₃. Thencompound g11 can be reduced in the presence of iron or zinc in aceticacid to yield the primary amine g12. Finally, g12 can then be coupled toacid chloride as exemplified earlier in Scheme 1.

In another embodiment of the present invention compounds of Formula(I-c) may be prepared according to the synthetic sequences illustratedin Scheme 4. Piperazine g14 can be acylated under standard conditions inthe presence of acid chloride. Then compound g16 can be reduced understandard hydrogenation conditions with Pt/C in primary amine g17.Finally, g17 can then be coupled to acid chloride as exemplified earlierin Scheme 1.

In another embodiment of the present invention compounds of Formula(I-c) may be prepared according to the synthetic sequences illustratedin Scheme 5. Piperazine g14 can be protected by (Boc)₂O, then reducedwith Pt/C and coupled with acid chloride under conditions well known fora person skilled in the art. After deprotection under acidic conditions,the secondary amine g22 can finally be acylated either by acid chlorideor carboxylic acid as exemplified earlier in Scheme 1.

Experimental

Unless otherwise noted, all starting materials were obtained fromcommercial suppliers and used without further purification.

Specifically, the following abbreviations may be used in the examplesand throughout the specification.

ACN (Acetonitrile) AcOEt (Ethyl acetate) (Boc)₂O (Di-tert-butylcarbonate) Cs₂CO₃ (Cesium carbonate) DCM (Dichloromethane) DIEA(Diisopropyl ethyl amine) DMAP (N,N-Dimethylaminopyridine) EDCI•HCl(1-3(Dimethylaminopropyl)-3- ethylcarbodiimide, hydrochloride) Et₃N(Triethylamine) Et₂O (Diethyl ether) EtOH (Ethanol) HCl (Hydrochloricacid) K₂CO₃ (Potassium carbonate) LCMS (Liquid Chromatography MassSpectrum) M (Molar) mg (Milligrams) MgSO₄ (Magnesium sulphate) μL(Microliters) mL (Milliliters) mmol (Millimoles) M.p. (Melting point)NaCl (Sodium chloride) NaHCO₃ (Sodium hydrogenocarbonate) NaOH (Sodiumhydroxide) Pt/C (Platinum on charcoal) THF (Tetrahydrofuran) TLC (Thinlayer chromatography) RT (Retention Time)

All references to brine refer to a saturated aqueous solution of NaCl.Unless otherwise indicated, all temperatures are expressed in ° C.(degrees Centigrade). All reactions are conducted not under an inertatmosphere at room temperature unless otherwise noted.

Most of the reaction were monitored by thin-layer chromatography on 0.25mm Merck silica gel plates (60E-254), visualized with UV light. Flashcolumn chromatography was performed on prepacked silica gel cartridges(15-40 μM, Merck).

Melting point determination was performed on a Buchi B-540 apparatus.

EXAMPLES Example 1 N-(3-Methoxyphenyl)thiophene-2-carboxamide (FinalCompound 2-1) Thiophene-2-carbonyl chloride

According to Scheme 1 Step 1: Thiophene-2-carboxylic acid (31.2 mmol,4.00 g) was slowly added to a solution of thionyl chloride (56.2 mmol,4.08 mL). The reaction mixture was stirred at room temperature for 1hour. After evaporation of the thionyl chloride, the crude product waspurified by bulb-to-bulb distillation (85° C., 14 Torr) to yieldthiophene-2-carbonyl chloride (23.7 mmol, 3.48 g, 76%) as a colorlessliquid.

N-(3-methoxyphenyl)thiophene-2-carboxamide

According to Scheme 1 Method A: A solution of thiophene-2-carbonylchloride (2.92 mmol, 0.31 mL) in DCM (1 mL) was added to solution of3-methoxyaniline (2.44 mmol, 0.27 mL) and DIEA (4.87 mmol, 0.87 mL) inDCM (4 mL) at 0° C. The reaction mixture was stirred at room temperaturefor 1 hour. The organic phase was washed with HCl 1 M solution, thenwith a saturated solution of NaHCO₃, was dried over MgSO₄, was filteredand was concentrated under reduced pressure to yieldN-(3-methoxyphenyl)thiophene-2-carboxamide (1.71 mmol, 0.40 g, 70%) as awhite solid. M.p.: 139-145° C.;

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=3.80 min; MS m/zES⁺=234.

Example 2 N-(3-Methoxyphenyl)picolinamide (Final Compound 2-3)

According to Scheme 1 Method B: 3-Methoxyaniline (1.62 mmol, 0.18 mL)was added to a solution of picolinic acid (1.62 mmol, 0.20 g), EDCI.HCl(2.44 mmol, 0.47 g), Et₃N (3.25 mmol, 0.45 mL), hydroxybenzotriazole(1.95 mmol, 0.30 g) in DCM (6 mL) at room temperature. The reactionmixture was stirred at 50° C. for 12 hours. The organic phase was washedwith a saturated solution of NaHCO₃ and with brine, was dried overMgSO₄, was filtered and was concentrated under reduced pressure. Thecrude product was purified by flash chromatography over silica gel usingcyclohexane/AcOEt (90:10) as eluent to affordN-(3-methoxyphenyl)picolinamide (1.46 mmol, 0.33 g, 90%) as an orangeliquid.

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=3.94 min; MS m/zES⁺=229.

Example 3 N-(3-(2-(2-Methoxyphenyl)-2-oxoethoxy)phenyl)picolinamide(Final Compound 2-9) N-(3-Hydroxyphenyl)picolinamide

According to Example 2: The title compound was prepared from3-aminophenol (18.0 mmol, 2.00 g). Reaction conditions: 12 hours at 50°C. 1.7 g (7.9 mmol, 43%) of N-(3-hydroxyphenyl)picolinamide wereobtained.

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=1.74 min; MS m/zES⁺=215.

N-(3-(2-(2-Methoxyphenyl)-2-oxoethoxy)phenyl)picolinamide

According to Scheme 2: K₂CO₃ (2.33 mmol, 323 mg) and2-bromo-1-(2-methoxyphenyl)ethanone (0.47 mmol, 107 mg) were addedsequentially to a solution of N-(3-hydroxyphenyl)picolinamide (0.47mmol, 100 mg) in acetone (3 mL). The reaction mixture was stirred at 50°C. for 14 hours. After filtration and evaporation, the crude product wasdiluted with water and with DCM. The organic phase was washed withbrine, was dried over MgSO₄, was filtered and was concentrated underreduced pressure. The crude product was triturated with Et₂O to obtainN-(3-(2-(2-methoxyphenyl)-2-oxoethoxy)phenyl)picolinamide (0.26 mmol, 94mg, 55%) as a yellow solid.

M.p.: 136-137° C.;

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=2.67 min; MS m/zES⁺=363.

Example 4 N-(3-Chloro-4-(3-chlorophenoxy)phenyl)picolinamide (FinalCompound 3-11) 2-Chloro-1-(3-chlorophenoxy)-4-nitrobenzene

According to Scheme 3 Step 1, Method A: 2-Chloro-1-fluoro-4-nitrobenzene(1.12 mmol, 0.20 g) was added to a suspension of 3-chlorophenol (1.02mmol, 0.10 mL), Cs₂CO₃ (1.25 mmol, 407 mg) in DMF/ACN (40:60, 3.6 mL).The reaction mixture was stirred at room temperature overnight. Thereaction mixture was quenched with water. The aqueous phase wasextracted with AcOEt. The organic phase was washed with brine, was driedover MgSO₄, was filtered and was concentrated under reduced pressure.The crude product was used without further purification to obtain2-chloro-1-(3-chlorophenoxy)-4-nitrobenzene (1.02 mmol, 288 mg, 100%) asan orange solid.

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=3.22 min.

3-Chloro-4-(3-chlorophenoxy)aniline

According to Scheme 3 Step 2: A suspension of iron (5.07 mmol, 283 mg),acetic acid (1.22 mmol, 70 μL) and of2-chloro-1-(3-chlorophenoxy)-4-nitrobenzene (1.02 mmol, 288 mg) inwater/EtOH (1:1, 8 mL) was stirred at 80° C. for 30 minutes. Afterevaporation of EtOH, the aqueous phase was basified with a saturatedsolution of NaHCO₃ and was extracted with AcOEt. The organic phase waswashed with brine, was dried over MgSO₄, was filtered and wasconcentrated under reduced pressure to yield3-chloro-4-(3-chlorophenoxy)aniline (1.02 mmol, 258 mg, 100%) as asolid. The product was used without further purification.

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=2.77 min; MS m/zES⁺=254.

N-(3-Chloro-4-(3-chlorophenoxy)phenyl)picolinamide

According to Scheme 3 Step 3: Picolinoyl chloride hydrochloride (1.52mmol, 271 mg) and Et₃N (3.05 mmol, 0.42 mL) were added sequentially to asolution of 3-chloro-4-(3-chlorophenoxy)aniline (1.02 mmol, 258 mg) inDCM (6 mL) at 0° C. The reaction mixture was stirred at room temperaturefor 2 hours. The organic phase was washed with a saturated solution ofNaHCO₃ and with brine, was dried over MgSO₄, was filtered and wasconcentrated under reduced pressure. The crude product was purified byflash chromatography over silica gel using cyclohexane/AcOEt (90:10) aseluent to afford N-(3-chloro-4-(3-chlorophenoxy)phenyl)picolinamide(0.52 mmol, 187 mg, 51%) as a white solid.

M.p.: 91.5-93.5° C.;

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=2.45 min; MS m/zES⁺=357.

Example 5 N-(3-Methoxy-4-(pyrimidin-2-yloxy)phenyl)picolinamide (FinalCompound 3-9) 2-(2-Methoxy-4-nitrophenoxy)pyrimidine

According to Scheme 3 Step 1 Method B: 2-Bromopyrimidine (1.26 mmol, 211mg) was added to a suspension of 2-methoxy-4-nitrophenol (1.15 mmol, 200mg), Cs₂CO₃ (1.41 mmol, 460 mg) in DMF (3 mL). The reaction mixture wasstirred at 80° C. for 3 days. The reaction mixture was quenched withwater. The aqueous phase was extracted with AcOEt. The organic phase waswashed with brine, was dried over MgSO₄, was filtered and wasconcentrated under reduced pressure. The crude product was washed with asolution of NaOH 3M and dried to obtain2-(2-methoxy-4-nitrophenoxy)pyrimidine (0.89 mmol, 220 mg, 78%) as asolid. The product was used without further purification.

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=1.89 min; MS m/zES⁺=248.

3-Methoxy-4-(pyrimidin-2-yloxy)aniline

According to Scheme 3 Step 2: A suspension of iron (4.45 mmol, 248 mg),acetic acid (1.07 mmol, 61 μL) and of2-(2-methoxy-4-nitrophenoxy)pyrimidine (0.89 mmol, 220 mg) in water/EtOH(1:1, 7 mL) was stirred at 80° C. for 30 minutes. After evaporation ofEtOH, the aqueous phase was basified with a saturated solution of NaHCO₃and was extracted with AcOEt. The organic phase was washed with brine,was dried over MgSO₄, was filtered and was concentrated under reducedpressure to yield 3-methoxy-4-(pyrimidin-2-yloxy)aniline (0.89 mmol, 193mg, 100%) as an oil. The product was used without further purification.

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=0.56 min; MS m/zES⁺=218.

N-(3-Methoxy-4-(pyrimidin-2-yloxy)phenyl)picolinamide

According to Scheme 3 Step 3: Picolinoyl chloride hydrochloride (1.33mmol, 256 mg) and Et₃N (2.67 mmol, 0.37 mL) were added sequentially to asolution of 3-methoxy-4-(pyrimidin-2-yloxy)aniline (0.89 mmol, 193 mg)in DCM (3 mL) at 0° C. The reaction mixture was stirred at roomtemperature for 2 hours. The organic phase was washed with a saturatedsolution of NaHCO₃. The aqueous phase was extracted with AcOEt. Theorganic phase was washed with brine, was dried over MgSO₄, was filteredand was concentrated under reduced pressure. The crude product waspurified by flash chromatography over C₁₈ column using water/ACN (70:30)as eluent to affordN-(3-methoxy-4-(pyrimidin-2-yloxy)phenyl)picolinamide (0.17 mmol, 55 mg,19%) as a white solid.

M.p.: 203-205° C.;

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=1.87 min; MS m/zES⁺=323.

Example 6 N-(3-Chloro-4-(4-isobutyrylpiperazin-1-yl)phenyl)picolinamide(Final Compound 4-2)1-(4-(2-Chloro-4-nitrophenyl)piperazin-1-yl)-2-methylpropan-1-one

According to Scheme 4 Step 1: Isobutyryl chloride (1.24 mmol, 0.13 mL)and Et₃N (2.48 mmol, 0.35 mL) were added to a solution of1-(2-chloro-4-nitrophenyl)piperazine (0.83 mmol, 200 mg) in DCM (5 mL)at 0° C. The reaction mixture was stirred at room temperature for 2hours. The organic phase was washed with a saturated solution of NaHCO₃.The aqueous phase was extracted with AcOEt. The organic phase was washedwith brine, was dried over Na₂SO₄, was filtered and was concentratedunder reduced pressure to afford1-(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)-2-methylpropan-1-one (0.83mmol, 261 mg, 100%). The product was used without further purification.

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=2.48 min; MS m/zES⁺=312.

1-(4-(4-Amino-2-chlorophenyl)piperazin-1-yl)-2-methylpropan-1-one

According to Scheme 4 Step 2: A solution of1-(4-(2-chloro-4-nitrophenyl)piperazin-1-yl)-2-methylpropan-1-one (0.62mmol, 195 mg) in EtOH (120 mL) was passed through a Pt/C 5% column in anH-Cube equipment (mode: Full). Then the solution was concentrated underreduced pressure to yield1-(4-(4-amino-2-chlorophenyl)piperazin-1-yl)-2-methylpropan-1-one (0.62mmol, 175 mg, 99%). The product was used without further purification.

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=1.56 min; MS m/zES⁺=282.

N-(3-Chloro-4-(4-isobutyrylpiperazin-1-yl)phenyl)picolinamide

According to Scheme 4 Step 3: Picolinoyl chloride hydrochloride (0.93mmol, 178 mg) and Et₃N (1.86 mmol, 0.26 mL) were added to a solution of1-(4-(4-amino-2-chlorophenyl)piperazin-1-yl)-2-methylpropan-1-one (0.62mmol, 175 mg) in DCM (3 mL) at 0° C. The reaction mixture was stirred atroom temperature for 2 hours. The organic phase was washed with asaturated solution of NaHCO₃. The aqueous phase was extracted withAcOEt. The organic phase was washed with brine, was dried over Na₂SO₄,was filtered and was concentrated under reduced pressure. The crudeproduct was purified by flash chromatography over C₁₈ column usingwater/ACN (60:40) as eluent to affordN-(3-chloro-4-(4-isobutyrylpiperazin-1-yl)phenyl)picolinamide (0.11mmol, 42 mg, 18%) as a white solid.

M.p.: 156-158° C.;

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=2.50 min; MS m/zES⁺=387.

Example 7 N-(3-Chloro-4-(4-propionylpiperazin-1-yl)phenyl)picolinamide(Final Compound 4-3) tert-Butyl4-(2-chloro-4-nitrophenyl)piperazine-1-carboxylate

According to Scheme 5 Step 1: A solution of1-(2-chloro-4-nitrophenyl)piperazine (2.90 mmol, 700 mg), Boc₂O (3.19mmol, 0.96 mL), Et₃N (3.48 mmol, 0.49 mL) and of DMAP (0.29 mmol, 35 mg)in DCM (5 mL) was stirred at room temperature overnight. The organicphase was washed once with HCl 0.1 M, once with water, once with brine,was dried over Na₂SO₄, was filtered and was concentrated under reducedpressure to afford tert-butyl4-(2-chloro-4-nitrophenyl)piperazine-1-carboxylate (2.50 mmol, 854 mg,86%). The product was used without further purification.

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=3.19 min; MS m/zES⁺=342.

tert-Butyl 4-(4-amino-2-chlorophenyl)piperazine-1-carboxylate

According to Scheme 5 Step 2: A solution of tert-butyl4-(2-chloro-4-nitrophenyl)piperazine-1-carboxylate (2.50 mmol, 854 mg)in EtOH (450 mL) was passed through a Pt/C 5% column in an H-Cubeequipment (mode: Full). Then the solution was concentrated under reducedpressure to yield tert-butyl4-(4-amino-2-chlorophenyl)piperazine-1-carboxylate (2.46 mmol, 766 mg,98%). The product was used without further purification.

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=2.37 min; MS m/zES⁺=312.

tert-Butyl 4-(2-chloro-4-(picolinamido)phenyl)piperazine-1-carboxylate

According to Scheme 5 Step 3: Picolinoyl chloride hydrochloride (3.68mmol, 656 mg) and Et₃N (7.37 mmol, 1.03 mL) were added to a solution oftert-butyl 4-(4-amino-2-chlorophenyl)piperazine-1-carboxylate (2.46mmol, 766 mg) in DCM (40 mL) at 0° C. The reaction mixture was stirredat room temperature for 1 hour. The organic phase was washed with asaturated solution of NaHCO₃. The aqueous phase was extracted withAcOEt. The organic phase was washed with brine, was dried over Na₂SO₄,was filtered and was concentrated under reduced pressure to affordtert-butyl 4-(2-chloro-4-(picolinamido)phenyl)piperazine-1-carboxylate(2.46 mmol, 1.02 g, 100%).

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=3.19 min; MS m/zES⁺=417.

N-(3-Chloro-4-(piperazin-1-yl)phenyl)picolinamide

According to Scheme 5 Step 4: HCl 4 M in dioxane (12.3 mmol, 3.07 mL)was added to a solution of tert-butyl4-(2-chloro-4-(picolinamido)phenyl)piperazine-1-carboxylate (2.46 mmol,1.02 g) in DCM (10 mL). The reaction mixture was stirred at roomtemperature overnight. After evaporation, DCM was added and then a NaOH1 M solution. The aqueous phase was extracted with DCM. The organicphase was washed with brine, was dried over MgSO₄, was filtered and wasconcentrated under reduced pressure. The crude product was purified byflash chromatography over silica gel using cyclohexane/AcOEt (60:40) aseluent to afford N-(3-chloro-4-(piperazin-1-yl)phenyl)picolinamide (0.97mmol, 308 mg, 40%) as an orange solid.

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=1.41 min; MS m/zES⁺=317.

N-(3-Chloro-4-(4-propionylpiperazin-1-yl)phenyl)picolinamide

According to Scheme 5 Step 5 Method A: A solution ofN-(3-chloro-4-(piperazin-1-yl)phenyl)picolinamide (0.19 mmol, 60 mg),propionic acid (0.19 mmol, 14 μL), EDCI.HCl (0.28 mmol, 54 mg), Et₃N(0.38 mmol, 53 μL) and of hydroxybenzotriazole (0.21 mmol, 32 mg) in DCM(5 mL) was stirred at room temperature for 1 day. The solution wasquenched with water. The aqueous phase was extracted with DCM. Theorganic phase was washed with brine, was dried over Na₂SO₄, was filteredand was concentrated under reduced pressure. The solid was trituratedwith water and finally with iPr₂O to affordN-(3-chloro-4-(4-propionylpiperazin-1-yl)phenyl)picolinamide (0.14 mmol,51 mg, 72%) as a yellow solid.

M.p.: 176-179° C.;

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=2.35 min; MS m/zES⁺=373.

Example 8 N-(4-(4-Benzylpiperazin-1-yl)-3-chlorophenyl)picolinamide(Final Compound 4-5)

According to Scheme 5 Step 5 Method B: A suspension of(bromomethyl)benzene (0.61 mmol, 74 μL),N-(3-chloro-4-(piperazin-1-yl)phenyl)picolinamide (0.51 mmol, 161 mg)and of K₂CO₃ (0.51 mmol, 70 mg) in ACN (3 mL) was stirred at 80° C. for30 minutes. After evaporation of the solvent, water and AcOEt wereadded. The aqueous phase was extracted with AcOEt. The organic phase waswashed with brine, was dried over Na₂SO₄, was filtered and wasconcentrated under reduced pressure. The crude product was purified byflash chromatography over silica gel using DCM/AcOEt (80:20) as eluentand finally crystallized in pentane to obtainN-(4-(4-benzylpiperazin-1-yl)-3-chlorophenyl)picolinamide (0.98 mmol, 40mg, 20%) as a white solid.

M.p.: 92-94° C.;

LC (Zorbax SB-C₁₈, 3.5 μm, 4.6×30 mm Column): RT=1.99 min; MS m/zES⁺=407.

The compounds in the following Tables have been synthezised according tothe same method as previous examples 1 to 5, as denoted in the columndenoted as “Exp. nr”. The compounds denoted with the asterisk have beenexemplified in the Examples.

TABLE 1 Compounds prepared according to the Examples.

Co. nr. Exp nr.

1-1 2

1-2 2

1-3 2

1-4 1

1-5 2

TABLE 2 Compounds prepared according to the Examples.

Co. nr. Exp nr.

B¹ B² 2-1 1*

H Me 2-2 3

H

2-3 2*

H Me 2-4 2

H Me 2-5 1

H Me 2-6 1

H CF₃ 2-7 3

H

2-8 3

H CH₂CH₂CH₂Ph 2-9 3*

H

2-10 3

H

2-11 3

H

2-12 3

H

2-13 1

H Me 2-14 1

F Me 2-15 3

H

2-16 2

H Me 2-17 1

F Me 2-18 1

F Me

TABLE 3 Compounds prepared according to the Examples.

Co. nr. Exp nr.

B¹ B² 3-1 4

H

3-2 1

Cl

3-3 2

Cl

3-4 1

Cl

3-5 4

N

3-6 4

Cl

3-7 4

Cl

3-8 1

Cl

3-9 5*

OMe

3-10 1

H —CF₃ 3-11 4*

Cl

3-12 4

Cl

3-13 4

Cl

3-14 4

Cl

3-15 4

Cl

3-16 4

Cl

TABLE 4 Compounds prepared according to the Examples.

Co. nr. Exp nr.

B¹

4-1 1

Cl

4-2 6*

Cl

4-3 7*

Cl

4-4 7

Cl

4-5 8*

Cl

Physico-Chemical Data LCMS-Methods:

LCMS were recorded on a Waters Micromass ZQ 2996 system by the followingconditions:

Reversed phase HPLC was carried out on an Zorbax SB-C18 cartridge (1.8μm, 4.6×30 mm) from Agilent, with a flow rate of 1.5 ml/min. Thegradient conditions used are: 90% A (water+0.05% of formic acid), 10% B(acetonitrile+0.05% of formic acid) to 100% B at 3.5 minutes, kept till3.7 minutes and equilibrated to initial conditions at 3.8 minutes until4.5 minutes. Injection volume 5-20 μL. ES MS detector was used,acquiring both in positive and negative ionization modes. Cone voltagewas 30 V for both positive and negative ionization modes.

All mass spectra were taken under electrospray ionisation (ESI) methods.

TABLE 5 Physico-chemical data for some compounds (nd = not determined).Melting MW RT Physical Co. Nr point (° C.) (theor) [MH⁺] (min) form 1-1nd 255.10 256 2.49 White solid 1-2 139-140 237.70 238* 4.23 White solid1-3 89.8-91.3 232.67 233 3.80 White solid 1-4 74-75 216.21 217 2.37Yellow solid 1-5 138-140 220.65 221 2.24 White solid 2-1   139-140.5233.29 234 3.80 White solid 2-2 148-149 339.32 340 2.42 White solid 2-3nd 228.25 229 3.94 Orange oil 2-4 87-89 248.30 249 3.85 Orange solid 2-553-57 234.27 235 2.20 White solid 2-6 79.5-80.5 282.22 283 2.80 Yellowsolid 2-7 139-140 366.80 367 2.81 Yellow solid 2-8 49-51 332.39 333 3.23White solid 2-9 136-137 362.38 363 2.67 Yellow solid 2-10 114.5-115.5362.38 363 2.63 White solid 2-11 118-121 350.34 351 2.64 Yellow solid2-12 nd 366.79 367 2.74 Yellow solid 2-13  98-101 232.23 233 2.16 Yellowsolid 2-14 nd 246.24 247 2.30 Brown solid 2-15  98-101 350.34 351 2.65Yellow solid 2-16 119-122 229.23 230 1.91 White solid 2-17 124-125264.23 265 2.39 White solid 2-18 103-105 252.26 253 2.19 White solid 3-2195-197 326.74 327 2.15 White solid 3-3 142-150 346.79 347 2.12 Whitesolid 3-4 154 332.76 333 2.10 Yellow solid 3-5 254-260 325.75 326 2.57Beige solid 3-6 102-104 360.74 361 3.03 Beige solid 3-7  99-101 359.21360 3.16 White solid 3-8 92-94 393.75 394 3.02 White solid 3-9 203-205322.32 323 1.87 Beige solid 3-11 91.5-93.5 359.21 360 3.35 White solid3-12 78-80 342.75 343 3.17 Yellow solid 3-13 104-105 342.75 343 3.10White solid 3-14 133-135 359.21 360 3.32 White solid 3-15 157-159 349.77350 2.90 Beige solid 3-16 223-228 350.76 351 2.06 Beige solid 4-2156-158 386.88 387 2.50 Beige solid 4-3 176-179 372.85 373 2.35 Yellowsolid 4-4 161-163 420.89 421 2.68 Yellow solid 4-5 92-94 406.91 407 1.99White solid

Pharmacology

The compounds provided in the present invention are positive allostericmodulators of mGluR4. As such, these compounds do not appear to bind tothe orthosteric glutamate recognition site, and do not activate themGluR4 by themselves. Instead, the response of mGluR4 to a concentrationof glutamate or mGluR4 agonist is increased when compounds of Formula I,I-a-d are present. Compounds of Formula I, I-a-d are expected to havetheir effect at mGluR4 by virtue of their ability to enhance thefunction of the receptor.

mGluR4 Assay on HEK-Expressing Human mGluR4

The compounds of the present invention are positive allostericmodulators of mGluR4 receptor. Their activity was examined onrecombinant human mGluR4a receptors by detecting changes inintracellular Ca²⁺ concentration, using the fluorescent Ca²⁺-sensitivedye Fluo-4-(AM) and a Fluorometric Imaging Plate Reader (FLIPR,Molecular Devices, Sunnyvale, Calif.)

Transfection and Cell Culture

The cDNA encoding the human metabotropic glutamate receptor (hmGluR4),(accession number NM_(—)000841.1, NCBI Nucleotide database browser), wassubcloned into an expression vector containing also the hygromycinresistance gene. In parallel, the cDNA encoding a G protein allowingredirection of the activation signal to intracellular calcium flux wassubcloned into a different expression vector containing also thepuromycin resisitance gene. Transfection of both these vectors intoHEK293 cells with PolyFect reagent (Qiagen) according to supplier'sprotocol, and hygromycin and puromycin treatment allowed selection ofantibiotic resistant cells which had integrated stably one or morecopies of the plasmids. Positive cellular clones expressing hmGluR4 wereidentified in a functional assay measuring changes in calcium fluxes inin response to glutamate or selective known mGluR4 orthosteric agonistsand antagonists

HEK-293 cells expressing hmGluR4 were maintained in media containingDMEM, dialyzed Fetal Calf Serum (10%), Glutamax™ (2 mM), Penicillin (100units/ml), Streptomycin (100 μg/ml), Geneticin (100 μg/ml) andHygromycin-B (40 μg/ml) and puromycin (1 μg/ml) at 37° C./5% CO₂.

Fluorescent Cell Based-Ca²⁺ Mobilization Assay

Human mGluR4 HEK-293 cells were plated out 24 hours prior to FLIPR³⁸⁴assay in black-walled, clear-bottomed, poly-L-ornithine-coated 384-wellplates at a density of 25,000 cells/well in a glutamine/glutamate freeDMEM medium containing foetal bovine serum (10%), penicillin (100units/ml) and streptomycin (100 μg/ml) at 37° C./5% CO₂.

On the day of the assay, the medium was aspirated and the cells wereloaded with a 3 μM solution of Fluo-4-AM (LuBioScience, Lucerne,Switzerland) in 0.03% pluronic acid. After 1 hour at 37° C./5% CO₂, thenon incorporated dye was removed by washing cell plate with the assaybuffer and the cells were left in the dark at room temperature for sixhours before testing. All assays were performed in a pH 7.4buffered-solution containing 20 mM HEPES, 143 mM NaCl, 6 mM KCl, 1 mMMgSO₄, 1 mM CaCl₂, 0.125 mM sulfapyrazone, 0.1% glucose.

After 10 s of basal fluorescence recording, various concentrations ofthe compounds of the invention were added to the cells. Changes influorescence levels were first monitored for 180 s in order to detectany agonist activity of the compounds. Then the cells were stimulated byan EC₂₅ glutamate concentration for an additional 110 s in order tomeasure enhancing activities of the compounds of the invention. EC₂₅glutamate concentration is the concentration giving 25% of the maximalglutamate response.

The concentration-response curves of representative compounds of thepresent invention were generated using the Prism GraphPad software(Graph Pad Inc, San Diego, USA). The curves were fitted to afour-parameter logistic equation:

(Y=Bottom+(Top−Bottom)/(1+10̂((Log EC₅₀ −X)*Hill Slope)

allowing determination of EC₅₀ values.

The Table 6 below represents the mean EC₅₀ obtained from at least threeindependent experiments of selected molecules performed in duplicate.

TABLE 6 Activity data for selected compounds Compound n° Ca²⁺ Flux* 2-4++ 1-2 ++ 1-3 +++ 2-5 ++ 2-6 ++ 2-7 ++ 2-8 ++ 2-9 ++ 2-10 ++ 2-11 ++2-12 ++ 2-13 ++ 2-14 +++ 1-5 ++ 2-15 ++ 2-16 ++ 2-17 ++ 3-2 +++ 2-18 ++3-4 ++ 3-5 +++ 3-8 ++ 4-3 ++ 4-4 ++ 3-15 +++ 4-5 ++ *Table legend: (+):EC₅₀ > 10 μM (++): 1 μM < EC₅₀ < 10 μM (+++): EC₅₀ < 1 μM

The results in Table 6 demonstrate that the compounds described in thepresent invention are positive allosteric modulators of human mGluR4receptors. These compounds don't have activity by themselves but theyrather increase the functional activity and/or maximal efficacy ofglutamate or mGluR4 agonist.

Thus, the positive allosteric modulators provided in the presentinvention are expected to increase the effectiveness of glutamate ormGluR4 agonists at mGluR4 receptor. Therefore, these positive allostericmodulators are expected to be useful for treatment of variousneurological and psychiatric disorders associated with glutamatedysfunction described to be treated herein and others that can betreated by such positive allosteric modulators.

Formulation Examples

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

In this Example, active ingredient can be replaced by the same amount ofany of the compounds according to the present invention, in particularby the same amount of any of the exemplified compounds.

2. Suspension

An aqueous suspension is prepared for oral administration so that each 1milliliter contains 1 to 5 mg of one of the active compounds, 50 mg ofsodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg ofsorbitol and water ad 1 ml.

3. Injectable

A parenteral composition is prepared by stirring 1.5% by weight ofactive ingredient of the invention in 10% by volume propylene glycol andwater.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

Reasonable variations are not to be regarded as a departure from thescope of the invention. It will be obvious that the thus describedinvention may be varied in many ways by those skilled in the art.

1. A compound having the Formula (I-b),

a pharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof,wherein: X¹ is N and X², X³ and X⁴ are each independently selected fromthe group of C, N, O, S and C═C representing a 5 or 6 memberedheteroaryl ring which may further be substituted by 1 to 3 radicalsA^(m); m is an integer ranging from 1 to 3; A^(m) radicals are eachindependently selected from the group of hydrogen, halogen, —CN, —OH,—NO₂, —CF₃, —SH, —NH₂ and an optionally substituted radical selectedfrom the group of —(C₁-C₆)alkyl, —(C₁-C₆)alkylhalo, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylcyano, —(C₁-C₆)alkylheteroaryl, —(C₁-C₆)alkylaryl, aryl,heteroaryl, heterocycle, —(C₀-C₆)alkyl-OR¹, —O—(C₂-C₆)alkyl-OR¹,—NR¹(C₂-C₆)alkyl-OR², —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR¹—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo-OR¹, —(C₁-C₆)alkylhalo-NR¹R², —(C₀-C₆)alkyl-S—R¹,—O—(C₂-C₆)alkyl-S—R¹, —NR¹—(C₂-C₆)alkyl-S—R², —(C₀-C₆)alkyl-S(═O)—R¹,—O—(C₁-C₆)alkyl-S(═O)—R¹, —NR¹—(C₁-C₆)alkyl-S(═O)—R²,—(C₀-C₆)alkyl-S(═O)₂—R¹, —O—(C₁-C₆)alkyl-S(═O)₂—R¹,—NR¹—(C₁-C₆)alkyl-S(═O)₂—R², —(C₀-C₆)alkyl-NR¹R², —O—(C₂-C₆)alkyl-NR¹R²,—NR¹—(C₂-C₆)alkyl-NR²R³—(C₀-C₆)alkyl-S(═O)₂NR¹R²,—O—(C₁-C₆)alkyl-S(═O)₂NR¹R², —NR¹—(C₁-C₆)alkyl-S(═O)₂NR²R³,—(C₀-C₆)alkyl-NR¹—S(═O)₂R², —O—(C₂-C₆)alkyl-NR¹—S(═O)₂R²,—NR¹—(C₂-C₆)alkyl-NR²—S(═O)₂R³, —(C₀-C₆)alkyl-C(═O)—NR¹R²,—O—(C₁-C₆)alkyl-C(═O)—NR¹R², —NR¹—(C₁-C₆)alkyl-C(═O)—NR²R³,—(C₀-C₆)alkyl-NR¹C(═O)—R², —O—(C₂-C₆)alkyl-NR¹C(═O)—R²,—NR¹—(C₂-C₆)alkyl-NR²C(═O)—R³, —(C₀-C₆)alkyl-OC(═O)—R¹,—O—(C₂-C₆)alkyl-OC(═O)—R¹, —NR¹—(C₂-C₆)alkyl-OC(═O)—R²,—(C₀-C₆)alkyl-C(═O)—OR¹, —O—(C₁-C₆)alkyl-C(═O)—OR¹,—(C₁-C₆)alkyl-C(═O)—OR², —(C₀-C₆)alkyl-C(═O)—R¹,—O—(C₁-C₆)alkyl-C(═O)—R¹, —NR¹—(C₁-C₆)alkyl-C(═O)—R²,—(C₀-C₆)alkyl-NR¹—C(═O)—OR², —(C₀-C₆)alkyl-O—C(═O)—NR¹R²,—(C₀-C₆)alkyl-NR¹—C(═NR²)—NR³R⁴, —(C₀-C₆)alkyl-NR¹—C(═O)—NR²R³,C₆)alkyl-NR¹—C(═O)—NR²R³, —NR¹—(C₂-C₆)alkyl-NR²—C(═O)—NR³R⁴ and—(C₀-C₆)alkyl-NR¹—C(═S)—NR²R³; Any two radicals of A^(m) (A¹ and A²) maybe taken together to form an optionally substituted 3 to 10 memberedcarbocyclic or heterocyclic ring; R¹, R², R³ and R⁴ are eachindependently hydrogen or an optionally substituted radical selectedfrom the group of —(C₁-C₆)alkylhalo, —(C₁-C₆)alkyl, —(C₁-C₆)alkylcyano,—(C₃-C₇)cycloalkyl, —(C₄-C₁₀)alkylcycloalkyl, heteroaryl,—(C₁-C₆)alkylheteroaryl, aryl, heterocycle and —(C₁-C₆)alkylaryl; Anytwo radicals of R (R¹, R², R³ or R⁴) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring; B¹ is selected from the group of hydrogen, halogen, —CN, —OH,—NO₂, —CF₃, —SH, —NH₂ and an optionally substituted radical selectedfrom the group of —(C₁-C₆)alkyl, —(C₁-C₆)alkylhalo, —(C₃-C₇)cycloalkyl,—(C₁-C₆)alkylcyano, —(C₁-C₆)alkylheteroaryl, —(C₁-C₆)alkylaryl, aryl,heteroaryl, heterocycle, —(C₀-C₆)alkyl-OR⁵, —O—(C₂-C₆)alkyl-OR⁵,—NR⁵(C₂-C₆)alkyl-OR⁶, —(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—O—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl, —NR⁵—(C₃-C₇)cycloalkyl-(C₁-C₆)alkyl,—(C₁-C₆)alkylhalo-OR⁵, —(C₁-C₆)alkylhalo-NR⁵R⁶, —(C₀-C₆)alkyl-S—R⁵,—O—(C₂-C₆)alkyl-S—R⁵, —NR⁵—(C₂-C₆)alkyl-S—R⁶, —(C₀-C₆)alkyl-S(═O)—R⁵,—O—(C₁-C₆)alkyl-S(═O)—R⁵, —NR⁵—(C₁-C₆)alkyl-S(═O)—R⁶,—(C₀-C₆)alkyl-S(═O)₂—R⁵, —O—(C₁-C₆)alkyl-S(═O)₂—R⁵,—NR⁵—(C₁-C₆)alkyl-S(═O)₂—R⁶, —(C₀-C₆)alkyl-NR⁵R⁶, —O—(C₂-C₆)alkyl-NR⁵R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶R⁷, —(C₀-C₆)alkyl-S(═O)₂NR⁵R⁶,—O—(C₁-C₆)alkyl-S(═O)₂NR⁵R⁶, —NR⁵—(C₁-C₆)alkyl-S(═O)₂NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵—S(═O)₂R⁶, —O—(C₂-C₆)alkyl-NR⁵—S(═O)₂R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶—S(═O)₂R⁷, —(C₀-C₆)alkyl-C(═O)—NR⁵R⁶,—O—(C₁-C₆)alkyl-C(═O)—NR⁵R⁶, —NR⁵—(C₁-C₆)alkyl-C(═O)—NR⁶R⁷,—(C₀-C₆)alkyl-NR⁵C(═O)—R⁶, —O—(C₂-C₆)alkyl-NR⁵C(═O)—R⁶,—NR⁵—(C₂-C₆)alkyl-NR⁶C(═O)—R⁷, —(C₀-C₆)alkyl-OC(═O)—R⁵,—O—(C₂-C₆)alkyl-OC(═O)—R⁵, —NR⁵—(C₂-C₆)alkyl-OC(═O)—R⁶,—(C₀-C₆)alkyl-C(═O)—OR⁵, —O—(C₁-C₆)alkyl-C(═O)—OR⁵,—NR⁵—(C₁-C₆)alkyl-C(═O)—OR⁶, —(C₀-C₆)alkyl-C(═O)—R⁵,—O—(C₁-C₆)alkyl-C(═O)—R⁵, —NR⁵—(C₁-C₆)alkyl-C(═O)—R⁶,—(C₀-C₆)alkyl-NR⁵—C(═O)—OR⁶, —(C₀-C₆)alkyl-O—C(═O)—NR⁵R⁶,—(C₀-C₆)alkyl-NR⁵—C(═NR⁶)—NR⁷R⁸, —(C₀-C₆)alkyl-NR⁵—C(═O)—NR⁶R⁷,—O—(C₂-C₆)alkyl-NR⁵—C(═O)—NR⁶R⁷, —NR⁵—(C₂-C₆)alkyl-NR⁶—C(═O)—NR⁷R⁸ and—(C₀-C₆)alkyl-NR⁵—C(═S)—NR⁶R⁷; B² is an optionally substituted aryl orheteroaryl; R⁵, R⁶, R⁷ and R⁸ are each independently hydrogen or anoptionally substituted radical selected from the group of—(C₁-C₆)alkylhalo, —(C₁-C₆)alkyl, —(C₁-C₆)alkylcyano,—(C₃-C₇)cycloalkyl, —(C₄-C₁₀)alkylcycloalkyl, heteroaryl,—(C₁-C₆)alkylheteroaryl, aryl, heterocycle and —(C₁-C₆)alkylaryl; Anytwo radicals of R (R⁵, R⁶, R⁷ or R⁸) may be taken together to form anoptionally substituted 3 to 10 membered carbocyclic or heterocyclicring; provided that: (i)

 cannot be

and provided that: (ii)

 cannot be

and provided that: (iii)

 cannot be


2. A compound according to claim 1, which can exist as optical isomers,wherein said compound is either the racemic mixture or one or both ofthe individual optical isomers.
 3. A compound according to claim 1,wherein said compound is selected from:N-(3,4-dichlorophenyl)-1H-pyrrole-2-carboxamideN-(3-Chlorophenyl)-1H-imidazole-2-carboxamideN-(3-Methoxyphenyl)thiophene-2-carboxamide5-Methyl-N-(4-phenoxyphenyl)furan-2-carboxamide Furan-2-carboxylic acid{3-[2-(4-fluoro-phenyl)-2-oxo-ethoxy]-phenyl}-amideN-(3-Methoxyphenyl)picolinamideN-(3-Methoxyphenyl)-2-methylthiazole-4-carboxamideN-(3-Chlorophenyl)thiophene-2-carboxamide5-Bromo-N-(3-methoxyphenyl)furan-2-carboxamideN-(3-Chlorophenyl)picolinamide N-(3-Methoxyphenyl)thiazole-2-carboxamideN-(3-(2-(3-Methoxyphenyl)-2-oxoethoxy)phenyl)furan-2-carboxamideN-(3-(2-Oxo-2-p-tolylethoxy)phenyl)furan-2-carboxamideN-(3-(2-(4-Methoxyphenyl)-2-oxoethoxy)phenyl)furan-2-carboxamideN-(3-(1-Oxo-1-p-tolylpropan-2-yloxy)phenyl)furan-2-carboxamideN-(3-(Trifluoromethoxy)phenyl)picolinamideN-(3-(2-(3-Chlorophenyl)-2-oxoethoxy)phenyl)picolinamideN-(3-(3-Phenylpropoxy)phenyl)picolinamideN-(3-(2-(2-Methoxyphenyl)-2-oxoethoxy)phenyl)picolinamideN-(3-(2-(3-Methoxyphenyl)-2-oxoethoxy)phenyl)picolinamideN-(3-(2-(3-Fluorophenyl)-2-oxoethoxy)phenyl)picolinamideN-(3-(2-(2-Chlorophenyl)-2-oxoethoxy)phenyl)picolinamideN-(3-Fluorophenyl)picolinamideN-(3-Methoxyphenyl)-5-methylisoxazole-3-carboxamideN-(4-Fluoro-3-methoxyphenyl)picolinamideN-(3-Chlorophenyl)-1H-pyrrole-2-carboxamideN-(3-(2-(2-Fluorophenyl)-2-oxoethoxy)phenyl)picolinamideN-(3-Methoxyphenyl)pyrimidine-4-carboxamide6-Fluoro-N-(4-fluoro-3-methoxyphenyl)picolinamideN-(3-Chloro-4-(pyrimidin-2-yloxy)phenyl)picolinamideN-(4-Fluoro-3-methoxyphenyl)thiazole-2-carboxamide and apharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof.
 4. Acompound according to claim 1, wherein said compound is selected from:N-(3-Chloro-4-(pyrimidin-2-yloxy)phenyl)-2-methylthiazole-4-carboxamideN-(3-Chloro-4-(pyrimidin-2-yloxy)phenyl)thiazole-2-carboxamideN-(3-Chloro-4-morpholinophenyl)picolinamideN-(3-Chloro-4-(pyridin-2-yloxy)phenyl)picolinamideN-(3-Chloro-4-(2,5-difluorophenoxy)phenyl)picolinamideN-(3-Chloro-4-(2-chlorophenoxy)phenyl)picolinamideN-(3-Chloro-4-(5-(trifluoromethyl)pyridin-2-yloxy)phenyl)picolinamideN-(3-Chloro-4-(4-isobutyrylpiperazin-1-yl)phenyl)picolinamideN-(3-Methoxy-4-(pyrimidin-2-yloxy)phenyl)picolinamideN-(4-(Trifluoromethoxy)phenyl)picolinamideN-(3-Chloro-4-(3-chlorophenoxy)phenyl)picolinamideN-(3-Chloro-4-(3-fluorophenoxy)phenyl)picolinamideN-(3-Chloro-4-(4-fluorophenoxy)phenyl)picolinamideN-(3-Chloro-4-(4-chlorophenoxy)phenyl)picolinamideN-(3-Chloro-4-(4-propionylpiperazin-1-yl)phenyl)picolinamideN-(4-(4-Benzoylpiperazin-1-yl)-3-chlorophenyl)picolinamideN-(3-Chloro-4-(4-cyanophenoxy)phenyl)picolinamideN-(3-Chloro-4-(3-cyanopyridin-2-yloxy)phenyl)picolinamideN-(4-(4-Benzylpiperazin-1-yl)-3-chlorophenyl)picolinamide and apharmaceutically acceptable acid or base addition salt thereof, astereochemically isomeric form thereof and an N-oxide form thereof.
 5. Apharmaceutical composition comprising a therapeutically effective amountof a compound according to claims 1 to 4 and a pharmaceuticallyacceptable carrier and/or excipient.
 6. A method of treating orpreventing a condition in a mammal, including a human, the treatment orprevention of which is affected or facilitated by the neuromodulatoryeffect of mGluR4 allosteric modulators, comprising administering to amammal in need of such treatment or prevention, an effective amount of acompound/composition according to claims 1 to
 5. 7. A method of treatingor preventing a condition in a mammal, including a human, the treatmentor prevention of which is affected or facilitated by the neuromodulatoryeffect of mGluR4 positive allosteric modulators, comprisingadministering to a mammal in need of such treatment or prevention, aneffective amount of a compound/composition according to claims 1 to 5.8. A method useful for treating or preventing central nervous systemdisorders selected from the group consisting of: addiction, tolerance ordependence, affective disorders, such as depression and anxiety,psychiatric disease such as psychotic disorders,attention-deficit/hyperactivity disorder and bipolar disorder;Parkinson's disease, memory impairment, Alzheimer's disease, dementia,delirium tremens, other forms of neurodegeneration, neurotoxicity, andischemia, comprising administering to a mammalian patient in need ofsuch treatment an effective amount of a compound/composition accordingto claims 1 to
 5. 9. A method useful for treating or preventing centralnervous system disorders selected from the group consisting ofParkinson's disease and movement disorders such as bradykinesia,rigidity, dystonia, drug-induced parkinsonism, dyskinesia, tardivedyskinesia, L-DOPA-induced dyskinesia, dopamine agonist-induceddyskinesia, hyperkinetic movement disorders, Gilles de la Tourettesyndrome, resting tremor, action tremor, akinesia, akinetic-rigidsyndrome, akathisia, athetosis, asterixis, tics, postural instability,postencephalitic parkinsonism, muscle rigidity, chorea and choreaformmovements, spasticity, myoclonus, hemiballismus, progressivesupranuclear palsy, restless legs syndrome, periodic limb movementdisorder, comprising administering to a mammalian patient in need ofsuch treatment an effective amount of a compound/composition accordingto claims 1 to
 5. 10. A method useful for treating or preventing centralnervous system disorders selected from the group consisting of cognitivedisorders: delirium, substance-induced persisting delirium, dementia,dementia due to HIV disease, dementia due to Huntington's disease,dementia due to Parkinson's disease, Parkinsonian-ALS demential complex,dementia of the Alzheimer's type, substance-induced persisting dementiaand mild cognitive impairment comprising administering to a mammalianpatient in need of such treatment an effective amount of acompound/composition according to claims 1 to
 5. 11. A method useful fortreating affective disorders, anxiety, Agoraphobia, Generalized AnxietyDisorder (GAD), Obsessive-Compulsive Disorder (OCD), Panic Disorder,Posttraumatic Stress Disorder (PTSD), Social Phobia, Other Phobias,Substance-Induced Anxiety Disorder, acute stress disorder comprisingadministering to a mammalian patient in need of such treatment orprevention, an effective amount of a compound/composition according toclaims 1 to
 5. 12. A method useful for treating or preventing centralnervous system disorders selected from the group consisting of mooddisorders: Bipolar Disorders (I & II), Cyclothymic Disorder, Depression,Dysthymic Disorder, Major Depressive Disorder, Substance-Induced MoodDisorder, comprising administering an effective amount of acompound/composition according to claims 1 to
 5. 13. A method useful fortreating or preventing neurological disorders selected from the group ofneurodegeneration, neurotoxicity or ischemia such as stroke, spinal cordinjury, cerebral hypoxia, intracranial hematoma, Parkinson's disease,memory impairment, Alzheimer's disease, dementia, delirium tremenscomprising administering to a mammalian patient in need of suchtreatment or prevention, an effective amount of a compound/compositionaccording to claims 1 to
 5. 14. A method useful for treating orpreventing inflammatory central nervous system disorders selected frommultiple sclerosis forms such as benign multiple sclerosis,relapsing-remitting multiple sclerosis, secondary progressive multiplesclerosis, primary progressive multiple sclerosis, progressive-relapsingmultiple sclerosis, comprising administering an effective amount of acompound/composition according to claims 1 to
 5. 15. A method useful fortreating migraine comprising administering an effective amount of acompound/composition according to claims 1 to
 5. 16. A method useful fortreating or preventing epilepsy and tremor, temporal lobe epilepsy,epilepsy secondary to another disease or injury e.g., chronicencephalitis, traumatic brain injury, stroke or ischemia comprisingadministering to a mammal in need of such treatment or prevention, aneffective amount of a compound/composition according to claims 1 to 5.17. A method useful for treating or preventing inflammation and/orneurodegeneration resulting from traumatic brain injury, stroke,ischemia, spinal cord injury, cerebral hypoxia or intracranial hematoma,comprising administering to a mammal in need of such treatment aneffective amount of a compound/composition according to claims 1 to 5.18. A method useful for treating or preventing sensory, motor orcognitive symptoms resulting from traumatic brain injury, stroke,ischemia, spinal cord injury, cerebral hypoxia or intracranial hematoma,comprising administering to a mammal in need of such treatment orprevention, an effective amount of a compound/composition according toclaims 1 to
 5. 19. A method useful for treating medulloblastomascomprising administering an effective amount of a compound/compositionaccording to claims 1 to
 5. 20. A method useful for treating orpreventing inflammatory or neuropathic pain comprising administering toa mammalian patient in need of such treatment an effective amount of acompound/composition according to claims 1 to
 5. 21. A method useful fortreating, or preventing, ameliorating, controlling or reducing the riskof various metabolic disorders associated with glutamate dysfunctioncomprising administering to a mammalian patient in need of suchtreatment an effective amount of a compound/composition according toclaims 1 to
 5. 22. A method useful for treating or preventing type 2diabetes comprising administering to a mammalian patient in need of suchtreatment an effective amount of a compound/composition according toclaims 1 to
 5. 23. A method useful for treating or preventing diseasesor disorders of the retina, retinal degeneration or maculardegeneration, comprising administering to a mammalian patient in need ofsuch treatment an effective amount of a compound/composition accordingto claims 1 to
 5. 24. A method useful for treating or preventingdiseases or disorders of the gastrointestinal tract includinggastro-esophageal reflux disease (GERD), lower esophageal sphincterdiseases or disorders, diseases of gastrointestinal motility, colitis,Crohn's disease or irritable bowel syndrome (IBS), comprisingadministering to a mammalian patient in need of such treatment aneffective amount of a compound/composition according to claims 1 to 5.25. Use of a compound according to claims 1 to 4 in the manufacture of amedicament for a treatment or prevention as defined in any of claims 6to
 24. 26. Use of a compound according to claims 1 to 4 to prepare atracer for imaging a metabotropic glutamate receptor.
 27. Use of acompound according to claims 1 to 4 as a taste agent, flavour agent,flavour enhancing agent or a food or beverage additive.